Despite its name, the Gila monster, a reptile native to the deserts of the United States and Mexico, does not live up to its reputation for ferocity; it is described as slow, clumsy, and stocky. Although it rarely attacks humans, its saliva contains potent toxins, and a bite can cause intense pain, with records of deaths caused by the venom.
In 1992, scientists investigated the venom of this animal and identified exendin-4, a peptide similar to GLP-1, a human intestinal hormone that regulates blood sugar levels. Tests in diabetic mice demonstrated that exendin-4 reduced glucose.
Subsequently, scientists collaborated with pharmaceutical companies Amylin and Eli Lilly to develop a synthetic version of this molecule, called exenatide, which was launched on the market in 2005. This milestone gave rise to a new class of drugs known as 'GLP-1 agonists' or 'GLP-1 analogs,' popularly referred to as 'weight loss pens,' although oral forms exist with effects beyond simple weight loss.
Medications such as Ozempic (semaglutide) and Mounjaro (tirzepatide) are prominent examples of this class. Initially developed to treat type 2 diabetes, a chronic condition affecting over 800 million people globally, they have proven equally effective in managing obesity and overweight.
These medications have transcended the clinical environment, becoming popular on social media and sold in informal groups. Due to aesthetic pressure and the desire for rapid weight loss, many people without a diagnosis of obesity or diabetes use the substance irregularly, without professional guidance.
This clandestine market makes it difficult to accurately quantify users of GLP-1 analogs. In Brazil, counterfeit and smuggled versions from Paraguay circulate without proper oversight or approval from Anvisa, posing a serious health risk. In the United States, it is estimated that 15% of the adult population has used or is using such medications, totaling over 40 million individuals. Consequently, obesity in the US has registered a decline, dropping from 42% to 40% of adults.
In the Brazilian context, Ministry of Health data indicates about 750,000 users, a number that is likely underreported. A survey conducted by the Locomotiva Institute revealed that 62% of Brazilians know someone who uses or has used weight loss pens, with one-third of respondents reporting that the treatment was administered by someone in their own household.
The trend points toward increased consumption, driven by the expiration of semaglutide's patent, the introduction of local and more affordable versions, and the possibility of inclusion in the SUS, as promised by Lula during his campaign. Furthermore, newer, more potent compounds are planned for future approval.
It is undeniable that we are witnessing an unprecedented phenomenon: the use of tens of millions of people worldwide of a new drug, often without continuous medical supervision. This constitutes a 'natural experiment' whose consequences are uncertain, shaping society decades after a discovery originating in the saliva of an unusual lizard.
Although inherent risks exist, even in approved versions, such as severe and rare side effects, indiscriminate use can cause unpredictable harm. However, this experiment also presents curious aspects. Patients report unexpected benefits beyond weight loss, citing cures for drug and alcohol addictions, improvements in mental health, cessation of migraines and chronic pain, enhanced attention and focus, reduction of menopausal symptoms, and increased libido.
This notoriety has generated online forums dedicated to the use of 'microdoses' of these drugs, below prescribed doses, aiming for various benefits, although such applications lack scientific proof. Although anecdotal reports do not constitute proof, they signal areas that warrant robust scientific investigation.
The scientific community is attentive to these thousands of reports, with research lines evaluating GLP-1 analogs to treat cardiovascular, renal, hepatic, neurodegenerative, autoimmune, and certain types of cancer conditions, many of which are in early but promising stages.
Alexandre Hohl, director of the Brazilian Association for the Study of Obesity and Metabolic Syndrome (Abeso), observes that 'it started with endocrinology and metabolism. Now, it seems all medical specialties are studying this.'
The ability of a single class of drugs to treat so many distinct pathologies seems extraordinary. However, the human body has not adapted to modern life; our ancestors were naturally selected in a hunter-gatherer lifestyle where food was scarce, programming the organism to store excess energy as fat.
The introduction of mass production of ultra-processed and high-calorie foods transformed this into a serious global public health problem. Currently, 2.6 billion adults worldwide suffer from overweight, including 940 million with obesity, representing one in seven people—a number that has doubled since 1990 and quadrupled among adolescents.
Dealing with excess weight is complex because the body tends to retain fat, and even after weight loss, metabolic and physiological changes persist for months or years. One of these factors is increased hunger after weight loss, as the organism, following savanna survival strategies, seeks to return to the previous state, characterizing obesity as a chronic disease.
The primary recommendation of science remains a combination of a balanced diet, caloric surplus, and exercise routine, supplemented by healthy habits such as adequate sleep and psychological support, although these are difficult to maintain.
Historically, medicine has explored pharmacological methods, such as substances that accelerate metabolism (like thyroid hormones or dinitrophenol), which cause weight loss but carry severe risks, including arrhythmias and dangerous increases in body temperature. Another approach involved anorexigens, derivatives of amphetamine, which act on the brain to reduce hunger, but show modest benefits and many adverse effects; sibutramine is the only drug of this type still in specific and supervised use.
Excluding bariatric surgery, which remains effective in the most severe cases, few interventions were satisfactory until the 1980s, when scientists began to understand the regulatory mechanisms of hunger, notably GLP-1. This advance was the result of a global scientific effort in universities and private companies.
To provide context, hormones function as chemical messengers that travel through the blood, connecting to specific receptors to give orders to organs. Upon ingesting food, intestinal L cells release GLP-1, which stimulates the pancreas to release insulin to store sugar. GLP-1 also slows gastric emptying, promoting a feeling of satiety, and acts on the brain to decrease appetite.
If synthetic GLP-1 were administered continuously, the urge to eat would be suppressed, leading to weight loss. The challenge lies in its short duration, as it is rapidly degraded by the DPP4 enzyme, with effects lasting a maximum of half an hour. Thus, researchers sought to create molecules analogous to GLP-1 but resistant to degradation. Exendin-4, extracted from the saliva of the Gila monster, served as inspiration due to its similar structure and ability to act as an agonist on the same receptors without being easily destroyed by DPP4.
Subsequently, a fatty acid was added to these molecules, allowing them to bind to blood albumin, ensuring a gradual and prolonged release of action. While previous analogs existed, such as liraglutide (daily application), the true revolution came with semaglutide, synthesized by Novo Nordisk, whose action lasts over a week, present in Ozempic, Wegovy, Ozivy, and Rybelsus.
Initially focused on glycemic control, the pens evolved when patients showed significant weight loss, leading to the development of specific formulations for weight loss with higher doses and remarkable efficacy. More recently, tirzepatide (the active ingredient in Mounjaro) emerged, developed by Lilly. Unlike being just a GLP-1 analog, it functions as a dual agonist, mimicking the GIP hormone as well. Tirzepatide helps control sugar and satiety, and in some cases, appears to enhance fat burning, resulting in greater weight loss than semaglutide in clinical studies.
It is important to note that these medications have side effects, such as nausea, vomiting, diarrhea, and gastrointestinal discomfort, which, although not severe, can prevent treatment for some individuals. Nevertheless, GLP-1 analogs have established themselves as a fundamental therapeutic tool in the fight against obesity.