🧙♂️ The Pharmacologist’s Guide to Tackling Obesity
There has been a lot of buzz around semaglutides recently. But do they really work? How do they work? Are they safe? Read on to learn about the pharmacologists solution to obesity.
It is well known that the world is facing an obesity crisis, particularly in industrialised nations. In fact obesity, defined as a body mass index (BMI) greater than or equal to 30 kg/m2, has tripled in the past 50 years. This condition is problematic for patients because it increases their probability of developing comorbidities such as high blood pressure, type 2 diabetes and certain types of cancer. In addition to the health related problems, obesity is estimated to account for 16-18% of total health expenditures in the US by 2023.
However, the traditional method of treating obesity, which involves changing lifestyle factors is difficult, time-consuming, and often ineffective. Consequently, there is a heightened demand for pharmacological interventions. This is where drugs such as semaglutide and liraglutide come in. Although they were originally developed as anti-diabetics, they have recently found a role in treating obesity. In this article we’ll discuss how exactly these medications work.
Are these medicines effective?
Several clinical trials have found that both semaglutide and liraglutide are more effective at causing weight loss than placebo, with semaglutide the superior drug of the two. The typical weight loss was around 5% for semaglutide across most clinical trials. A maximum of 15% weight reduction was reported. None of the clinical trials saw weight gain with these drugs. However, these trials were conducted with mostly caucasian participants. Consequently, more work needs to be done to understand the effects of these drugs in people of other ethnicities.
What are the general effects ?
The physiological effects, meaning the symptoms, that these drugs cause have been extensively documented and observed through several clinical trials conducted on liraglutide and semaglutide. In general, it has become clear that these drugs cause a reduction in food consumption without affecting the taste. In addition, these drugs have been shown to increase insulin secretion and reduce glucagon secretion, which is a hormone that stimulates a reduction in blood sugar levels. So it’s unsurprising why these drugs were first used to treat diabetic patients. The main question now is how exactly do these physiological effects arise? What is the mechanism behind the reduction in appetite?
Foreword on GLP-1 receptor agonists
Collectively, semaglutide and liraglutide fall under the category of GLP-1 receptor agonists. All this means is that both drugs activate the GLP receptor, which stands for glucagon-like peptide. Yep, it was first discovered because it binds to a peptide (protein) that is similar to glucagon. I know … shocking. As you can tell, pharmacologists are a bunch of super creative and imaginative people. Anyway, you may be wondering what exactly a receptor is. In essence a receptor is a protein that binds to a molecule and passes on a message to the inside of the cell, which causes the cell to do something in response. I like to imagine the cell as a medieval fortress ruled by a paranoid king that likes to keep all the gates to his castle closed so that no-one can travel inside or out. But the king still needs to know what is going on in the outside world so he allows his scouts to post letters through a flap in the city gates. Receptors are like this flap, they allow information to flow into the cell, whilst preventing the molecule that is carrying this information from getting in.
It is this flow of information, mediated by GLP-1 receptors, that causes its effect. The problem is we don’t know what happens with the letter once it gets inside the castle. In real cells, there is a cascade. The receptor will activate a molecule, which will activate a different molecule and then that one will activate a third molecule and so on. This is the part that is still largely unknown because the GLP-1s have been developed relatively recently, with the first human clinical trial for liraglutide only being conducted in 2002. However, it should be noted that a failure to understand the mechanism does not prevent a pharmaceutical from being approved or from being effective. Indeed, the mechanism of paracetamol, one of the most widely used drugs on earth, is still a topic of debate within the pharmacological community.
Despite this, there have been some studies that have suggested possible mechanisms for liraglutide. In general, the proposed mechanism falls under two umbrellas, peripheral and central. This is a little bit of pharmacological jargon that basically means acting outside of the central nervous system (brain and spine) or inside the central nervous system.
Mechanism for the central effects
Just as a reminder, the main central effect of these drugs is hunger suppression. GLP-1 receptors have been found in the brainstem, which is at the back of your head and connects the brain to the spine. The neurons here send several projections to parts of the brain that are associated with appetite and homeostasis. Further studies have shown that the administration of GLP-1s into the brain (third intracerebroventricular administration) causes a reduction in appetite and body weight. This study then went on to demonstrate that blocking these receptors had the opposite effect.
In particular, it has been suggested that the long-term liraglutide treatment stimulates activation of POMC/CART by the projections from the brain stem. POMC/CART are a type of neuron found in the central part of the brain that has been found to reduce hunger, energy intake and food cravings.
Alongside this, there have also been reports of peripherally regulated appetite suppression. For example one study showed that blocking the peripheral receptors caused an increase in food consumption. Similar to the central effects. Consequently, it’s likely that appetite suppression has both central and peripheral elements. However it should be noted that these studies were conducted in rats
However, what about humans you may be wondering? Unfortunately there is not very much research in this area. Probably because of the difficulties of studying living human brain tissue and the recent focus on the use of these drugs for diet suppression. However, one study showed that obese individuals had increased brain responses to pictures of food in the areas of the brain that regulate reward in comparison to non-obese individuals. The experimenters later demonstrated that this heightened response was blocked by administration of a GLP-1 agonist. This supports the view that human appetite suppression is controlled by similar mechanisms to that of rat models.
Mechanism for peripheral effects
Having looked at the central effects, what are the peripheral effects of GLP-1 receptors? These are primarily increased insulin secretion and decreased glucagon secretion, which helps to reduce blood glucose levels. I am glad to say our knowledge of these pathways is better although still not entirely satisfactory.
Insulin is produced by beta cells in the pancreas. GLP-1 receptors have been found on these cells, which allows our liraglutide and semaglutide scouts to get their message to the psychotic king.
It is thought that the GLP-1 receptor activates an excitatory cascade that causes a flood of calcium ions into the cell, which unlike the GLP-1 messages actually cross the castle walls and enter the cell. Importantly, the calcium signals for the insulin to be excreted out of the. Perhaps we could imagine this as a gate being opened to trade with insulin for calcium, a precious commodity, with foreign merchants. After all, the king's greed would probably outweigh his paranoia.
In contrast, it is unlikely that glucagon suppression will be caused by a direct interaction with a GLP-1 receptor. Instead, it has been proposed that GLP-1 agonists activate receptors on delta cells (a neighbouring Queendom), which then secretes somatostatin, which is a peptide hormone. This hormone then inhibits the alpha cells (these are the ones that produce glucagon), which prevents glucagon from being secreted. This can be visualised as the queen sending out an army to suppress the foreign territories with her somatostatin soldiers.
Are GLP-1 receptor drugs safe ?
In the latest review article on PubMed, which integrates several clinical trials, some of which have over a thousand participants, there have been no reported dangerous side effects. However, some people do experience nausea, and, less frequently, vomiting and diarrhea. Importantly, these drugs do not cause a dangerous level of blood-glucose drop even in patients without diabetes. There are some concerns that GLP-1 agonists could cause pancreatic cancer because they cause beta cell proliferation. However, the rate of pancreatic cancers observed in clinical trials was not above the expected rate for the population size. Consequently, it would appear that these drugs are physiologically safe. Having said this, I want to make clear that you should always seek professional medical advice before taking any medication.
Discussion
In summary, it has been established that semaglutide and liraglutide safely cause weight loss in people with obesity. Furthermore, it is likely that this weight loss is caused by a simultaneous suppression of appetite and an increase in insulin secretion. However, I want to make clear that this is not a wonder drug. In most studies a 5% reduction in body weight occurred. This is unlikely to make many obese people un-obese. Furthermore, one clinical trial has shown that when people were taken off the drug, they regained much of the weight they lost.
One year after withdrawal of once-weekly subcutaneous semaglutide 2.4 mg and lifestyle intervention, participants regained two-thirds of their prior weight loss, with similar changes in cardiometabolic variables.
Instead these drugs have been designed to help people maintain weight lost through healthy eating, exercise, etc. Consequently, it’s clear that this medication alone is not enough. Instead, this medication should be viewed as an aid towards reaching a healthier weight in conjunction with a healthy lifestyle.
Yegor Lisle (he/him) is a UCL MSci Pharmacology student. He is curious about the nature of biology, the origin of life, and the biochemistry of the universe. In particular he wants to understand more about the interface between biology, chemistry and physics.