“Slimming Miraculous Drug” Semaglutide, Can It Really Solve the Obesity Crisis?
Martin Whyte
Associate Professor of Metabolic Medicine, University of Surrey, UK
Introduction
In recent years, Semaglutide, as a GLP-1 analog, has attracted attention due to its significant weight loss effects and multiple health benefits for obese patients. The cause of obesity is complex, involving multiple factors such as genetics, environment, and socio-economic conditions. Although GLP-1 drugs have shown great potential in the short term, their long-term effects, side effects, and adaptability to different patients still need further validation. Can the long-term safety and effectiveness of Semaglutide and other GLP-1 drugs be guaranteed? Faced with possible side effects and weight rebound after stopping the medication, how should patients and doctors balance the pros and cons of drug use?
Overview:
About one-eighth of the global population consists of obese patients, and newly developed weight-loss medications seem to bring new hope to this group.
Semaglutide is an analog of intestinal hormone glucagon-like peptide-1 (GLP-1), which sends satiety signals to the brain.
Semaglutide appears to be safe and effective, but further testing is required.
Scientists do not yet fully understand the exact mechanism of GLP-1 drugs.
Solving the obesity epidemic cannot rely solely on medications but must address the multiple internal and external factors that lead to obesity.
Recently, the “slimming miraculous drug” Semaglutide has frequently appeared in the news with its superior results in treating obesity and clinical effects that capture attention. Semaglutide is an analog of intestinal hormone glucagon-like peptide-1 (GLP-1). Currently, about one-eighth of the global population is obese, so the emergence of Semaglutide seems like a “miracle.” But can obesity, this complex disease, really be solved by just one “miracle drug”?
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#1 Anti-obesity medications can make obese patients healthier — True
Glucagon-like peptide 1 (GLP-1) receptor agonists have significant health benefits for patients.
A phase 2 clinical trial by Danish pharmaceutical company Novo Nordisk (STEP 2) showed that taking 2.4 mg of Semaglutide weekly could reduce about 15% of body weight over 68 weeks.
In addition to weight loss, GLP-1 drugs significantly improve patients’ health: lowering blood pressure and triglyceride levels, reducing glycosylated hemoglobin levels by an average of 1.4%. It also reduces the risk of cardiovascular disease. Compared to placebo, GLP-1 drugs can reduce the likelihood of major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke) by 12-14% in type 2 diabetes patients. However, although GLP-1 has a significant weight loss effect, its impact on cholesterol is minimal.
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However, GLP-1 drugs have serious side effects that affect patients’ ability to continue medication
Gastrointestinal side effects are the most common. About 10%-20% of people may experience nausea and vomiting, of which only half will feel relief after a year. GLP-1 drugs also increase heart rate, but specific body damage caused by this is not clear.
GLP-1 drugs increase the risk of gallstones. Regardless of the reason, rapid weight loss makes people prone to gallstones, even with very low-calorie diets. In addition, 20%-40% of the weight lost with GLP-1 drugs is muscle. Preventing muscle loss has become a major focus of current research.
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So far, it cannot be confirmed whether the clinical benefits of GLP-1 drugs outweigh the risks
Although GLP-1 drugs have been around for a while, their widespread use has only been in recent years. It will take several more years for us to have a better understanding of their long-term safety.
Clinical studies on animals show that GLP-1 drugs may slightly increase the risk of thyroid cancer, but there is currently no solid evidence. For patients with a history of or a family history of thyroid cancer, doctors need to think twice before prescribing GLP-1 drugs.
The situation after patients stop using GLP-1 drugs is also worth paying attention to. About two-thirds of people experience weight regain after stopping the medication. Gradually stopping the medication may help some patients maintain their health, but some may need long-term medication.
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#2 We have a clear understanding of the mechanism of GLP-1 drugs — False
Over the past 20 years, there has been significant progress in understanding the mechanisms by which the human body maintains weight.
Current concepts are vastly different from the past, where everyone knows that the cause of obesity is not “eating and being lazy.” The mechanisms of weight change are not within human willpower. Just like breathing—people can briefly hold their breath, but the nervous system will eventually force them to breathe. Some people can lose weight significantly through crash diets, but after a period, their weight will automatically return to previous levels. Dietary studies repeatedly show that no matter what diet method is used, most dieters will regain weight about a year later. Over the years, individual weight changes are minimal.
The human body’s weight maintenance mechanism is based on complex neural circuits centered on the midbrain and hindbrain regions. These areas are responsible for integrating signals related to energy balance, regulating food intake, and energy expenditure. We now also know that weight maintenance is closely related to signals from the intestines. Weight-loss surgeries (such as gastric bypass surgery) have demonstrated this. Studies have shown that post-surgery weight loss is not due to a “reduced absorption of food” but because the surgery triggers the release of intestinal hormones (such as GLP-1). Under the combined action of these hormones, the body sends out satiety signals earlier.
Image source: PI France
Semaglutide, as a GLP-1 analog, leverages the relationship between intestinal signals and weight. It can better bind to albumin and resist enzyme degradation, thus staying longer in the bloodstream. Past similar drugs could only result in 5%-8% weight loss for patients.
In the future, a “cocktail therapy” for obesity may be developed, with multiple drugs performing specific roles, simulating different physiological signals, and ultimately achieving results similar to gastric bypass surgery.
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Although we know that Semaglutide is effective, the specific mechanism is still unclear
The human body’s weight maintenance system has many “redundancies”—if one signal pathway is blocked, the signal will still be transmitted through other pathways. Therefore, it is difficult to determine the exact role of each mechanism segment and what signals have gone wrong in obese patients.
GLP-1 can act on the brain, pancreas, and stomach, but these actions are not prioritized. For obese patients, we know that GLP-1 delays stomach emptying, but it is unclear how much different it is compared to hypothalamic signals. Additionally, GLP-1 receptors are present in the heart, lungs, and kidney tissues.
Another emerging anti-obesity drug, tirzepatide, is a dual agonist of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors, reflecting the complexity of the human body’s weight maintenance system. GIP itself prevents fat loss, but when combined with GLP-1, it has additional weight-loss effects. In clinical trials, patients taking 10 or 15 mg of tirzepatide weekly lost about 20% of their weight in 72 weeks. This could be because GIP increases the receptor occupancy of GLP-1, but the specific reasons are still unclear.
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Not all of the effects of GLP-1 have been fully explored
Although GLP-1 drugs can indeed help with weight loss and improving health, there are still some unknown effects, such as anti-inflammatory effects, etc.
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#3 Anti-obesity medications will alleviate the public health crisis of obesity — False
Indeed, many genes can lead to obesity
In addition to the genetic information contained in the genes themselves, gene expression (epigenetics) also influences a person’s weight. Anti-obesity medications help counteract biological signals within the body that lead to weight regain.
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But genetics is not the only factor, external factors also lead to obesity
External factors include social pressure, socio-economic factors, access to healthy food, environmental pollution, etc., and their impact should not be underestimated. People worldwide are gradually transitioning from physical labor to office work, spending more time sitting motionless in front of computers, which can also lead to obesity.
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Therefore, we cannot rely on GLP-1 drugs to solve all problems
Over the past three to four decades, human living environments have become increasingly “obesogenic,” requiring concerted efforts from society as a whole to make changes. If all overweight and severely obese patients rely on so-called “miracle drugs,” the root problem will never be solved.
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Marianne Guenot
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Meister Xia
