Reacción a "Reactions: Science chooses obesity drugs as the 2023 Breakthrough of the Year"

Almost two decades have passed (since 2005) since the family of GLP-1 analogs has been used for the treatment of patients with type 2 diabetes who also have obesity (BMI>30kg/m²). Over the years, various molecules belonging to this family have been used (exenatide, liraglutide, dulaglutide, semaglutide), with common effects on diabetes control, but with some molecule-dependent differences, such as potency in reducing body weight. This has led to a new line of clinical studies to evaluate the role of these drugs in obesity without associated diabetes, given their primarily cerebral effects on appetite control and the digestive tract (slowing stomach emptying), among other effects on peripheral organs (such as the liver, kidney, and heart). Currently, the GLP-1 analogs approved for obesity treatment in both adults and adolescents (>12 years old) are liraglutide and semaglutide. Semaglutide (Wegovy) is notably more potent, achieving approximately 15% total weight loss, a historic percentage not previously reached with medications, except with bariatric surgery (commonly known as "stomach reduction," although it is more complex than that). It's essential to note that these molecules not only affect weight but have also demonstrated cardiovascular protective effects (SELECT study) and renal effects (FLOW study), as well as effects on fatty liver, which are significant complications of obesity.

Today, we know that obesity is not a moral disease; it does not depend on the individual's willpower but is a chronic and recurrent condition with high cardiovascular mortality, cancer, and associated diseases, resulting from excess fat tissue with negative health effects. This excess fat tissue can be caused by genetic, biological factors (such as hormonal imbalances, etc.), psychological, environmental, and socioeconomic factors, all leading to disruptions in appetite control (due to hormone imbalances in the brain, originating from the intestine, such as GLP-1, or from fat tissue, such as leptin, etc.) and metabolism (low calorie-burning capacity, related to genetics, muscle mass, genetics, etc.).

It is also noteworthy that, primarily through studies explaining responses to bariatric surgery (>20% total body weight lost), scientists have learned more about the response and effects of nutrient-stimulated intestinal peptides (GLP-1, GIP, glucagon) in obese patients. This, coupled with the development of artificial intelligence, has allowed the rapid development of a broad range of obesity medications in a few years, based on combinations of agonists for these peptides. Most are in clinical trial phases, but one, Tirzepatide, a dual GLP-1+GIP agonist, has shown weight loss of >20% in people with obesity due to the combined effects of GLP-1 and GIP. Tirzepatide is currently approved for type 2 diabetes with obesity and is in the process of approval for obesity. In the final stages of clinical trials are triple agonists (GLP-1+GIP+Glucagon) showing approximately 25% total weight loss potency, dual GLP-1+Glucagon agonists, etc.

One of the most important questions is how long the treatment should last. This question would not exist if not for the belief that obesity is a lifestyle condition caused by bad habits and lack of individual will. No one questions when medication is withdrawn from a patient with diabetes or cancer. Ultimately, obesity is a chronic disease with multiple causes, complex biological alterations requiring chronic treatment. Additionally, we need to learn how to manage these powerful new medications not only for weight loss but also for remission of comorbidities. Recent data suggests that after several years of treatment, discontinuing GLP-1 analogs results in weight gain, but to a lesser extent, and not all lost weight is regained, indicating that these drugs somehow have the potential to rebalance biology. Nevertheless, these are very preliminary data, more hypotheses to be expanded and proven.

Many aspects remain to be defined, one of which is the ability to phenotype our patients with obesity and determine the most suitable treatment for each specific case.

It is possible that in the coming year, the award for the discovery of the year will be granted to intestinal peptide analog drugs, not just GLP-1 analogs, which, despite being the most potent now, will be surpassed in potency by combinations such as dual and triple agonists.