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What’s next in the era of Ozempic, the popular weight loss drug?
Photo: Karolina Grabowska – Pexels
Few drugs have achieved the stardom that semaglutide, marketed in the United States as Ozempic or Wegovy, has today. This synthetic, injectable version of an intestinal hormone is the emblem of a new category of drugs initially developed as a treatment for diabetes and which rose to prominence on the medical and public scene as an effective weapon against obesity. Semaglutide has turned out to be so successful that the producing laboratory, the Danish company Novo Nordisk, cannot meet the demand.
The US Food and Drug Administration (FDA) approved semaglutide in 2017 to improve the control of blood sugar levels in adults with type 2 diabetes and, years later, in June 2021, for the treatment of obesity or overweight in people with related risk factors, such as high blood pressure or diabetes.
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Social media boosted fame of the medication: in mid-2022 TikTok users viralized a clip in which it was said that Kim Kardashian had used semaglutide to lose eight kilos and be able to wear an iconic Marilyn Monroe dress at the MET gala in New York. In the following months, everyone from former British Prime Minister Boris Johnson to billionaire businessman Elon Musk acknowledged having turned to medication to combat late-night binges or look fit. Today, three out of four Americans say that Have you heard of these medications? —and, of them, more than half consider that it is a good option for losing weight, according to a Pew Research survey—.
But last November, cardiologists were the ones with their eyes set on the drug. At the opening of the 2023 American Heart Association annual meeting in Philadelphia, the presentation of the results of a clinical study generated tremendous interest: semaglutide, apparently, was a new tool for treating heart disease.
The study, called SELECT, was carried out in 41 countries, on more than 17,000 people who were overweight or obese and at high cardiovascular risk, but without diabetes. And it found that a weekly subcutaneous injection of 2.4 milligrams of semaglutide can, in addition to helping people lose an average of 15% of their original weight, reduce the risk of heart attack, stroke or death by 20%. It is a type of effect that puts it in the same category as other medications that prevent cardiovascular events, such as low-dose aspirin, antihypertensives, or blood-lowering statins. cholesterol.
From the study, scientists can deduce the number of people that need to be treated to produce the desired benefit in one of them, a measure of efficiency similar to the one that a soccer team could use that calculates how many shots on goal on average their team must make. players so that one of them ends in a goal. In this case, scientists calculate that, if 67 patients without diabetes, but who are overweight or obese and at high risk of suffering a cardiovascular event, are treated for 40 months, a major cardiovascular event, such as a heart attack, a stroke or a heart attack, will be avoided. death from heart disease. For comparison, this is the same number of patients with a cardiovascular history who must take aspirin o drugs for hypertension for 60 months to avoid a single stroke.
Based on the results of the study, in early March The FDA approved the use of injectable semaglutide to reduce the risk of cardiovascular deathmyocardial infarction and stroke in adults with cardiovascular disease and who are obese or overweight.
“It is a milestone. For the first time we have a medication, semaglutide, that not only causes weight loss, but also reduces the formation of atherosclerotic plaque and prevents deaths and cardiovascular events,” says Paola Harwicz, a cardiologist and obesity specialist based in Buenos Aires, who He directed the Cardiometabolism Council of the Argentine Society of Cardiology and participated in the meeting in Philadelphia. Several studies demonstrate the effectiveness of the drug in reducing atherosclerotic plaque formation, including one performed in patients with type 2 diabetes in which, after four months of treatment with semaglutide, the thickness of the carotid artery, a clinical marker of atherosclerosis, was reduced by 13%.
A role for semaglutide and other related drugs in preventing cardiovascular disease—the cause of one in three deaths worldwide—further boosts the prospects of these drugs on the market and expands the universe of specialists who could prescribe them. Furthermore, it repositions being overweight or obese as one of the main truly modifiable risk factors for cardiovascular disease.
Deal with extra kilos
According to the classic medical approach, to lose weight there must be an imbalance between the calories that are ingested and those that are burned: either you eat less or you spend more. However, in the last 30 years, new evidence has shown that it is much more complicated, says Julio César Montero, nutritionist and president of the Argentine Society of Obesity and Eating Disorders.
The emerging thinking among those who work in this field, and collected in a statement from the Endocrine Societyis that obesity is due to two related but distinct processes: the aforementioned energy imbalance (eating more calories than the body expends) and the reestablishment of the “target” body weight—the weight that the body determines as its goal. — at an increased value.
People with obesity present a disorder of the energy homeostasis system, which is the biological process that maintains weight stability through the active adaptation of energy intake to energy expenditure over time. Thus, the body responds to weight loss by tenaciously trying to regain the lost kilos and return to its target weight—of increased value.
The mechanism behind the body’s quest to return to its initial weight is not yet fully understood, but it explains why it is so difficult to achieve an effective treatment to manage obesity. It is estimated that only one in five people who, with diet and exercise, lose between 5% and 10% of their initial weight over the course of six months manage to maintain it beyond a year. A more sedentary lifestyle and the wide range of ultra-processed foods It has made it even more difficult to lose weight and maintain that loss. It is projected that for 2035 More than half of the world’s population could be overweight or obese.
Until now, the traditional anti-obesity drugs have been found to have limited effectiveness. Most act on brain chemical signals—neurotransmitters—to reduce appetite, an approach pioneered in the 1960s by amphetamine and continued to this day by some derivatives and other safer drugs. Another medication is orlistat (also marketed as Alli or Xenical), which reduces the absorption of fat from food.
But for all of these drugs, the effects in the short and medium term are relatively modest, achieving a reduction of between 6% and 10% of initial weight. Furthermore, adverse effects, from insomnia, nervousness and increased blood pressure, to diarrhea or fecal incontinence, limit its more widespread use.
Hormones, the gut and the brain
In search of new ways to understand and treat obesity, in recent decades scientists have turned their gaze to the hormones secreted by the intestine.
Specifically, the focus of the research has been on a dozen hormones that have roles around optimizing the process of digestion and absorption of nutrients from the foods we eat.
The new strategy “has changed the therapeutic landscape of obesity to target the underlying mechanisms” and has promoted “an auspicious new era of highly effective medicines”note endocrinologist Ania Jastreboff of Yale School of Medicine and her colleague Robert Kushner of Northwestern University in an article in the 2023 Annual Review of Medicine.
One of those hormones is glucagon-like peptide 1 or GLP-1, discovered in the 1980s. Semaglutide, the active molecule in Ozempic and Wegovy, is a synthetic version of GLP-1 that mimics its action. Like GLP-1 and another drug, liraglutide, launched on the market in 2010, it suppresses the release of glucagon—a hormone secreted by the pancreas to raise blood sugar levels. It also promotes the growth and function of pancreatic beta cells, responsible for producing insulin, the hormone that ensures that sugar from food enters the body’s cells to give them energy.
Both mechanisms regulate blood sugar levels and explain why these medications were initially designed to combat diabetes. A series of clinical studies called SUSTAINwho evaluated the drug in about 8,000 patients with type 2 diabetes, showed that semaglutide is more effective than other available drugs (sitagliptin, marketed as Januvia; exenatide or Byetta; dulaglutide or Trulicity, and insulin glargine or Lantus) in reducing the values of glycosylated hemoglobin —a test that measures the average level of glucose or sugar in the blood over the last three months. Maintaining blood sugar levels within ideal values is a goal in the treatment of diabetes to avoid complications of the disease.
But it was soon realized that these drugs came with a bonus, given that GLP-1 not only acts on the pancreas. It also acts on brain centers that control appetite, and decreases stomach movements and emptying, so people feel full for longer. Together, these mechanisms contribute to reducing food intake, but, unlike old anti-obesity medications, “they do so in a more physiological way, with few adverse effects,” says Montero. One of the best effects, she adds, is that they relieve suffering, because they calm the anxiety to eat. The patients report a lower desire to consume highly seasoned and salty foods, or foods rich in flour, as well as better control over cravings.
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For Harwicz, semaglutide can be a facilitator that helps people make better decisions. One of his patients, a man weighing more than 300 pounds with a history of diabetes who had failed multiple attempts to lose weight, was able to lose 80 pounds—more than 20 percent of his body weight—with weekly injections of the drug, along with food education and a tailored physical activity plan. “He really feels like he’s making it because the medication is helping him,” he says. “It is important to modify your lifestyle, medication is not something magical. But people can choose their meals better and reduce the amount of what they eat with much more peace of mind.”
Of course, like any drug, semaglutide does not work in all patients nor is it tolerated by all. In the SELECT study, for example, 16.6% of participants receiving semaglutide discontinued the trial due to adverse effects, primarily digestive problems such as nausea, vomiting, and diarrhea.
What’s coming
All indications are that injected semaglutide is just the beginning in this new era of weight loss drugs. In addition to a oral version of semaglutide in high doses that showed promising effects in studies and is expected to soon be approved, a tsunami of results from clinical trials of new drugs that also operate on the gut-brain axis and recreate the action of other intestinal and pancreatic hormones is anticipated.
One of them is glucose-dependent insulinotropic polypeptide (GIP), which promotes the release of insulin after meals and also reduces appetite. Another hormone is glucagon, which counterbalances the action of insulin by raising blood sugar levels, helps eliminate fat from the liver and increases satiety. And a third is amylin, which delays stomach emptying, accelerates satiety and reduces the desire to eat.
Together they have been called “treatments based on nutrient-stimulated hormones” because they mimic the action of hormones that are released or function when specialized cells that act as sensors in the digestive tract detect the ingestion of food. And they promise to enhance the slimming effects, alone or combined, even through a physiological reset that prevents the body from stubbornly returning to a kind of weight range to which it seems predestined. In other words, it reduces the body’s tendency to regain lost kilos.
One of these new drugs, tirzepatide (marketed as Mounjaro or Zepbound), from Eli Lilly, which acts on both the GLP-1 and GIP receptors, obtained FDA approval in November 2023 to treat obesity. One of the studies Clinical trials of this drug showed that it produced an average decrease of 25.3% of initial weight in those who received a weekly injection for 88 weeks.
Another experimental drug from Eli Lilly, retatrutide, nicknamed “triple G” because it acts on GLP-1, GIP and glucagon receptors, could be next on the list. In June 2023, a study led by Jastreboff showed weight loss never seen with a drug. Patients without diabetes, for example, averaged a loss of 24% of their body weight in just 48 weeks (11 months). And in the group with the highest dose, a quarter of the patients lost more than 30%, which is close to the results of bariatric surgery, highly effective for weight loss, but more drastic.
“I never imagined doctors would have to worry about our patients losing too much weight by taking an anti-obesity drug,” Kushner says. “This is truly an exciting turning point in the science and practice of obesity, a major paradigm shift in how we think about and manage people living with obesity.”
Kushner and Jastreboff suggest in their paper that combining several of these hormone-based drugs could target the many intertwined mechanisms of obesity. Montero agrees: “There is a swarm of hormones that form a spider web. And touching more than one thread at a time can move the spider web better, enhancing the effect and making the interventions more comfortable, with fewer adverse events,” he says.
Semaglutide and tirzepatide, on the other hand, could also provide benefits in treating other diseases, such as alcohol abuse disorder and other compulsive or addictive behaviors, such as smoking, uncontrolled shopping, or nail biting. The drugs too reduce inflammation, which could help limit damage to different organs and structures, such as the kidney or joints. There are also preliminary studies on the drug’s effects in preventing cancer or in the treatment of parkinson and of Alzheimer’s, although more studies are still required to confirm them. The Science editors They noted that no scientific advance of 2023 had been so transformative in so many fields, impacting everything from financial markets to popular culture.
But, like all medical innovation, there are also unavoidable challenges on the horizon. Although the visible adverse effects of synthetic versions of GLP-1—such as nausea, vomiting, constipation, and diarrhea—are usually mild and limited to the gastrointestinal tract, other more unusual but serious complications have raised some concern, such as a possible increased risk of pancreatitis. Additionally, animal studies (not yet proven in humans) suggest there is a link to thyroid cancer risk.
Another barrier is the cost of these medications. In the United States, monthly treatment with semaglutide costs almost $1,000, while the price drops almost 10 times in countries such as Japan, the United Kingdom and Australia. In Latin America, where obesity rates have grown faster than in the rest of the world’s regions, the drug remains poorly accessible to the majority of the population. In Argentina, for example, in March an Ozempic pen that allows you to apply four doses of 1 mg cost 409,000 Argentine pesos, which is equivalent to more than two minimum wages in that country. Taking into account that the dose used in the SELECT study was 2.4 mg per week, a little more than two pens per month would be needed to cover that dose.
In addition, studies show that the benefits on weight fade or decrease sharply when treatment is stopped, which is why it should be continued long term. For example, research published in 2022 found that patients They regain two-thirds of the weight they lost within a year of stopping the medication.
“Our enthusiasm as clinicians with these drugs decreases if we think about it from the point of view of public health,” says Patricio López Jaramillo, endocrinologist, researcher and rector of the University of Santander, in Bucaramanga, Colombia. In his opinion, the use of medications must be framed in a broader social context that goes beyond “the rational, linear and disciplinary vision of medical specialists.”
“New anti-obesity drugs should be considered a useful tool if financial access is improved,” he says. And its use “must be framed within global actions and programs that allow populations to have real possibilities of practicing healthy lifestyle habits, such as exercising, following a varied diet and not smoking.”
Kushner says the lifestyle advice given to people using these new medications needs to be reexamined, de-emphasizing calorie counting or daily scale records. For example, we should focus more on health outcomes than weight loss, encourage the consumption of high-quality protein, and emphasize the importance of physical activity and resistance exercise to preserve muscle mass.
One option might be to use tests to predict which patients will do better with different medications and who, perhaps, should consider surgery or other approaches. “Not all patients respond to treatment,” explains Andrés Acosta, an Ecuadorian doctor and researcher who leads the Obesity Precision Medicine Laboratory from the Mayo Clinic, in Rochester, New York. That is why it is important to identify those who would benefit the most, he adds.
Acosta, for now, co-founded a company that in 2023 launched a test that identifies patients with a trait they call “hungry gut,” and that characterizes those people who quickly move food from the stomach and Consequently, they lose satiety faster. That could be a subgroup that would particularly benefit from these new drugs. For an anti-obesity drug market that could reach $100 billion by 2030, it doesn’t hurt to ensure that resources are invested in the patients who will be able to get the most out of it.
*The article was originally published in Knowable Magazine.
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