According to Geloneze, medications based on GLP-1 hormone analogues are safe but should only be used under medical supervisionLéo Ramos Chaves / Revista Pesquisa FAPESP
Bruno Geloneze, an endocrinologist from the University of Campinas (UNICAMP), specializes in metabolic diseases— disorders associated with the way the body processes proteins, carbohydrates, and fats from food. He supports the use of GLP-1 analogues, a promising new class of weight-loss medications, although he has some reservations. Produced naturally in the intestine and in smaller quantities in the brain immediately after meals, GLP-1 is a hormone that stimulates the production of insulin, reduces blood glucose levels when they are high, and causes a feeling of satiety.
“Medication alone cannot solve the problem of obesity. As with any weight-loss regimen, it makes you lose fat, but also muscle, which is not desirable,” says the researcher. “It should be used alongside a change in dietary behavior, and preferably with some degree of physical activity.” The group of drugs, initially designed to treat diabetes, contains synthetic versions of GLP-1.
Because they are highly similar to the natural hormone, the molecules in the drugs stimulate the same effects as GLP-1, but with one big difference: they remain functional for longer than the natural hormone, which only has an impact on the body for between 10 and 15 minutes. Depending on the formulation and dosage, drugs based on GLP-1 analogues, such as liraglutide and semaglutide, remain active for days, or even a week.
In an interview given at the Obesity and Comorbidities Research Center (OCRC), one of the Research, Innovation, and Dissemination Centers (RIDCs) funded by FAPESP, Geloneze outlines the risks and benefits of this new class of drugs.
Are the effects of GLP-1 analogues very different from those of older drugs used to manage obesity?
Older medications did not respond to the current definition of obesity, which is a chronic, relapsing, neurochemical disease. In other words, treating it requires a three-pronged intervention: it has to act on the central nervous system, be usable for a long time, and thus be capable of preventing a return to obesity. Some past medications were potent but could not be used chronically because they caused very intense side effects or chemical dependency. People became addicted to the drug. Others could be administered for a longer period of time, but they did not prevent weight gain from recurring. The major success of this new class of drugs is that they effectively tackle these three issues.
Are studies on these new drugs still too recent to support their prolonged use?
There are people who have been using them for more than 10 years, since the moment they were launched. The first versions of these drugs were designed to manage type 2 diabetes, but they ended up being used to tackle obesity because they promote weight loss — informally at first, and then in a more regulated approach. Some scientific studies have analyzed the cardiovascular impact of these drugs for five years. A controlled study that observes the effects of a drug for two years is considered long-term. In the past, the effects of other weight-loss drugs, which were not from the GLP-1 analogue class, were monitored for just a few weeks or months. We can therefore say that the long-term use of GLP-1 analogues is safe.
Why are they more effective and safer?
Because their method of action is very specific, while older medications, most of which acted on neurotransmitters such as serotonin and noradrenaline, have more widespread effects. These older drugs affect the regions of the brain that influence hunger and satiety, but also many other unwanted locations. This results in side effects and chemical dependency, regardless of whether the drug leads to weight loss or not.
Patients taking these new drugs say they do not feel hungry for most of the day. They always feel half-full
How does the GLP-1 hormone function in the human body?
When we eat, food passes through our digestive tract and we produce GLP-1 for three reasons. The first is to send a signal to insulin-producing cells in the pancreas that nutrients are arriving. This signal itself does not increase insulin production, it just makes the cells that produce it extremely sensitive to slight changes in blood glucose (the amount of sugar in the blood). The second is to slow down gastric emptying, a mechanism that results in a feeling of fullness, and consequently, satiety. The third reason is to send a message to the brain to tell us to stop eating.
How is this message sent?
The GLP-1 hormone travels to the hypothalamus via the bloodstream and the vagus nerve [a cranial structure that controls vital functions, such as heart rate, blood pressure, breathing, and movements of the digestive tract, and reflexes, such as coughing, vomiting, and swallowing]. In the hypothalamus, the blood-brain barrier only allows certain nutrients to pass, but it is slightly more permeable to GLP-1. When the hormone reaches the brain, it acts specifically on the hunger and satiety center, unlike the neurotransmitters that were stimulated by older medications.
GLP-1 analogues are synthetic molecules. Do they act in the same way as the hormone naturally produced by the human body?
Yes. The big difference is that GLP-1 analogues continue to affect the body for much longer than the natural hormone, which has a half-life of about 10 minutes. Older medicines from other classes lasted six hours, at most. But GLP-1 analogues act for between 24 and 144 hours. The effect of liraglutide lasts for less time than that of semaglutide. These medications can only be used with a prescription from a doctor and must be administered by the patient themselves in the form of an injection. They stimulate the nervous system for the entire time that they are active, giving the person a slight feeling of satiety all day long. Patients taking these drugs say they do not feel hungry for most of the day. They always feel half-full. When they start eating, they start to feel satiated faster and their hunger in general decreases. Some even complain that they feel less desire to consume alcoholic beverages, which is also good for weight loss, since alcohol is very high in calories. The main side effect of these drugs is that they slightly slow down gastric emptying, which can cause abdominal discomfort and nausea. This bothers some people.
Is this the main side effect?
It is a mild, bearable side effect. The vast majority of people get used to it and learn to live with it. If they find it unbearable, we can reduce the dose to try to find a balance where the medication provides the benefits without the side effects. Between 5% and 10% of people are unable to tolerate the medications and cannot use them. But that is true of any drug. One advantage of this class of medicine is that the patient can immediately stop taking the drug and the side effects will disappear within a maximum of one week.
Is it safe to stop taking them for a while and then start taking them again?
Yes. They do not create chemical dependency and using them does not alter the natural production of GLP-1. There is no evidence that using these synthetic drugs causes the body to produce more or less natural GLP-1 when the patient stops taking them. Likewise, they do not lose effectiveness if their use is interrupted and then resumed. They can be used intermittently. But I don’t like to classify them as long-term treatment options. I prefer to say that they can be part of a long-term approach for the issue of obesity. If a patient is maintaining good control of their weight in a given month, doing more exercise and following a balanced diet, they can stop using the medication during that period and then resume taking it again if they later lose control of their weight again. But it is important to be careful with intermittent use — it can lead patients to experience a yo-yo effect, losing weight while taking the medication and gaining weight when they stop. This is not good for their health.
Many of the studies on these new drugs are supported by the pharmaceutical industry that produces them. Could this cause people to distrust the research results?
Brazil actively participates in international multicenter studies of these new drugs. I myself took part in an international study on the effects of liraglutide. We always use a double-blind system, meaning I do not know if I am giving the person a placebo or the medicine, and the patient does not know which they are receiving. The studies are also audited by regulatory agencies, such as the FDA [US Food and Drug Administration]. The process is not foolproof or without flaws, but why would a government agency favor one manufacturer over another? Yes, there is a management network that ensures that studies — even those sponsored by private companies — can be trusted. They are supported by the laboratories in terms of funding. But everything is heavily audited. Are there flaws in the system? If they exist, someone should identify them and that will have repercussions. Often, one laboratory inspects another — its competitor. When manipulation can occur is when disclosing information to the lay public, giving more prominence to certain aspects and trying to sweep less positive details under the rug.
Older medications did not respond to the current definition of obesity, which is a chronic, relapsing, neurochemical disease
Last year, there was a proposal to offer liraglutide, the patent of which is expiring this year, through Brazil’s Public Health System (SUS). Is this a measure that you would you be in favor of?
In principle, I am not in favor of offering these medications via SUS without a structured treatment plan. Alone, they do not help anyone lose weight in a healthy way. As with any weight-loss regimen, they make you lose fat, but also muscle, which is not desirable. The patient can also become malnourished if they are not properly advised. The medicine should be used alongside a change in dietary behavior, and preferably with some degree of physical activity to maintain muscle mass. So if SUS does decide to offer these medications, it should also offer a process of behavioral and dietary education. But that doesn’t exist at the moment.
What is your opinion on the arsenal of drugs available to manage obesity?
In Brazil, there are only four approved medications: orlistat [formerly Xenical]; sibutramine, initially developed as an antidepressant; a unique combination of two drugs that have been used for a long time, one to help quit smoking [bupropion] and the other to treat alcoholism [naltrexone], which together stimulate serotonin production; and three GLP-1 analogues (liraglutide, semaglutide, and tirzepatide). When taken with a meal, orlistat blocks the absorption of up to 30% of the ingested fat. But this is a lot of fat elimination and it can cause adverse effects, such as flatulence, diarrhea, and fatty stools. These are not dangerous side effects, but they are unpleasant. The drug helps patients lose weight, but only to a small degree, less than 5% of bodyweight. Sibutramine is a serotonin reuptake inhibitor. It reduces appetite a little, but is not recommended for people with cardiovascular problems. Bupropion and naltrexone are medications that affect the mesolimbic system, linked to the sensation of craving and addiction. Combining the two must be done with caution, since together they function as an antidepressant and can have impacts on the entire brain. Finally, there are the GLP-1 analogues.
What is the difference between the three GLP-1 analogues?
In Brazil, medications are currently being sold containing different dosages of liraglutide and semaglutide, which were approved by ANVISA [the Brazilian Health Regulatory Agency] to treat diabetes or help with weight loss. The same synthetic molecule can be used in more than one medicine, at different dosages. These different drugs are therefore taken at different frequencies, have effects of differing intensity, and remain in the body for different lengths of time. Liraglutide [the active ingredient in the brand-name medicines Victoza and Saxenda] can help a person lose up to 10% of their bodyweight. Semaglutide [sold under the brand names Ozempic and Wegovy, the latter scheduled to go on sale in August] generally has more of an effect, resulting in 10% to 20% weight loss. It is important to note that it is very difficult to remain 10% lighter in the long term. That is true for both slim and obese people.
What about tirzepatide?
Tirzepatide was approved by ANVISA last year for the treatment of diabetes [with the commercial name Mounjaro] and leads to even greater weight loss. The difference is that it acts as an analogue of GLP-1 and also of GIP, another hormone associated with insulin production and the feeling of satiety. However, tirzepatide is not yet available in Brazil. There is now a great demand for GLP-1 analogues in the developed world and a lack of products on the international market. A month-long four-injection course of some of these drugs, such as semaglutide at a dosage of 1 milligram, costs around one thousand reais. It is an expensive medicine.
For what kind of patient profile do you recommend these drugs?
There are set rules for prescribing weight-loss drugs. People with a body mass index [BMI] of 30 or more are considered obese and are theoretically eligible for medication. But it is possible that these drugs could also be useful for people with a lower BMI, down to 25 or 27, who are typically described as being overweight but not obese. The most important thing is to identify whether the person, even if they are not extremely overweight, has comorbidities associated with obesity. There are several subtypes of obesity. There are therefore researchers who currently prefer to talk about obesities in the plural. It is important to know these subtypes in order to establish priorities. Not to increase the number of people to be treated with drugs, but to exclude individuals who at a given moment are not a priority for being medicated.
What are the main subtypes of people with obesity?
We can make an initial distinction between two major groups of people with obesity: those whose metabolism is within the expected range or with generally good results in cholesterol, glucose, and hypertension tests, and those with an unhealthy metabolism. There are also individuals who are only slightly overweight but have significant comorbidities. People, for example, who only appear to be carrying a bit of extra weight, but who already have fat in the liver and could develop cirrhosis. Finally, there are people who only have subcutaneous fat, but no metabolic changes. So the approach to managing obesity has to go far beyond the mere issue of the scales or aesthetics. Future treatments will need to focus primarily on transforming people who are only slightly obese but have many comorbidities into individuals who only face serious health problems if they gain a lot of weight.
Are these new drugs already having an impact on the so-called global obesity epidemic?
The impact on the obesity epidemic has been very small. But the existence of these drugs and the attention they are getting shines a spotlight on many of the issues we discuss at our RIDC. They can be used as a form of motivation to talk about topics that normally do not get much media coverage and do not attract much attention in society. Today we live in an obesogenic environment that facilitates weight gain due to sedentary lifestyles and the consumption of ultra-processed foods. Many people, even in the medical sector, still do not understand that obesity is a chronic disease that causes health problems. In about five years, I think there will be drugs available that are even more selective than GLP-1 analogues. These drugs will be capable of controlling the production of certain types of fat, such as visceral fat, which is concentrated in the abdomen and is harmful to health. Along with other public health measures, they will be important in tackling the obesity epidemic.
