Another Endorsement by Musk: Is the Weight Loss Supplement Truly Miraculous?

Wegovy, which has sparked discussions on social media, is a GLP-1 receptor agonist medication. GLP-1 drugs have now become a goldmine for pharmaceutical giants Novo Nordisk and Eli Lilly, propelling Novo Nordisk to become the most valuable company in Europe, surpassing LVMH Group.

It is said that by sticking to a weekly injection, weight can be reduced by 15%. Celebrities like Elon Musk have praised it on various platforms. These new types of weight-loss drugs are not just cosmetic products; they will benefit billions of ordinary people worldwide who struggle with obesity.

According to statistics, more than one-fifth of the global population is overweight or obese. The World Obesity Federation predicts that by 2035, this number will increase to over 4 billion, with over half of the population facing overweight or obesity issues.

Obesity is a medical condition, and glucagon-like peptide-1 (GLP-1) drugs are currently recognized as scientifically effective treatments. For the past few decades, the approach to tackling obesity has primarily focused on encouraging lifestyle changes rather than medication. This is because previous methods of drug treatment for weight loss were ineffective or unreliable. However, the understanding of obesity as a true medical condition that can lead to diabetes, heart disease, hypertension, stroke, gout, and various cancers is changing. With the development and commercialization of new drugs like Novo Nordisk's Wegovy, there are now scientifically effective treatments available, specifically GLP-1 receptor agonist drugs.

GLP-1 is currently a mainstream research target in the field of weight loss, with a market space exceeding 100 billion dollars. The global market size for GLP-1 receptor agonists has already surpassed 20 billion dollars, and J.P. Morgan predicts that by 2030, approximately 15 million obese patients will be using GLP-1 drugs, with annual sales exceeding 100 billion dollars. The sales in the U.S. market alone are expected to approach 50 billion dollars.

According to Jefferies, the market size for these drugs is expected to exceed $150 billion by 2031. This is comparable to the sales of all cancer drugs combined, which is approximately $185 billion. In other words, GLP-1 drugs will become as widespread as beta-blockers or statins.

Obesity is influenced by various factors such as evolution, genetics, environment, diet, and lifestyle. Modern lifestyles characterized by excessive food supply, high-calorie processed foods, sedentary behavior, and modern habits contribute to obesity. Many people resort to dieting for weight loss, but the body often fights to regain weight by slowing down metabolism. This leads to a gradual decrease in the amount of food one can consume without gaining weight, making it challenging to sustain dieting efforts.

On the other hand, GLP-1RA medications offer multiple benefits, including lowering blood sugar, regulating blood lipid levels, controlling weight, and reducing blood pressure. Compared to other approaches, they have a higher success rate in achieving blood sugar targets and a lower risk of hypoglycemia.

GLP-1 is a hormone-like medication that can bind to specific receptors and participate in regulating and maintaining stable blood sugar levels through multiple pathways. Its actions include promoting insulin secretion, inhibiting excessive glucagon secretion, and delaying gastric emptying. Additionally, GLP-1 can increase satiety. Clinical studies have shown that sustained activation of GLP-1 receptors is associated with weight loss. In other words, GLP-1 can integrate nutritional signals to control food intake, energy absorption, and assimilation.

When blood sugar levels rise, GLP-1 binds to receptors (GLP-1 receptors) on pancreatic beta cells and achieves biological regulation through four main ways: 1) promoting insulin secretion and biosynthesis; 2) promoting the proliferation and neogenesis of pancreatic beta cells; 3) inhibiting apoptosis of pancreatic beta cells; 4) reducing endoplasmic reticulum stress and inhibiting cellular metabolic disorders. Additionally, GLP-1 can also regulate blood sugar levels by binding to receptors on pancreatic alpha cells or indirectly inhibiting the secretion of glucagon from alpha cells.

GLP-1 receptor-dependent intracellular signaling pathways in pancreatic beta cells. GLP-1R activation is involved in insulin secretion and biosynthesis (green), beta cell proliferation and neogenesis (blue), inhibition of cell apoptosis (red), and alleviation of endoplasmic reticulum stress (purple).

GLP-1 receptors are not only present in pancreatic cells but also expressed in multiple tissues such as the gastrointestinal tract, heart, skin, and nervous system. GLP-1 exerts its effects through inhibiting gastric emptying and gastric acid secretion, influencing the central nervous system, reducing appetite, and inducing satiety, thereby achieving weight control through various pathways.

Furthermore, GLP-1 binds to other target organs involved in insulin action, such as the liver, skeletal muscle, and adipose tissue, promoting glycogen synthesis and fat formation in these respective tissues, leading to blood pressure and lipid-lowering effects while protecting the cardiovascular system.

GLP-1 can also act on the central nervous system, enhancing learning and memory functions, thereby providing neuroprotection.

GLP-1 receptor agonists (GLP-1RAs) have a significant role in diabetes treatment, particularly in reducing cardiovascular risks. Cardiovascular disease (CVD) is a major cause of mortality in diabetes patients and is influenced by multiple factors. Controlling cardiovascular risk factors can significantly reduce the risk of cardiovascular events. Therefore, the new concept of diabetes management also emphasizes reducing the CVD risk in diabetes.

The American Diabetes Association emphasizes the evidence of GLP-1RAs in reducing cardiovascular risks and recommends their use. According to a study, compared to other glucose-lowering medications, GLP-1RA drugs, especially liraglutide, semaglutide, and dulaglutide, have clear cardiovascular benefits. They exert cardiac protective effects through multiple mechanisms, thereby improving cardiovascular safety and reducing CVD risk.

If Novo Nordisk's key CVOT study, SELECT, proves that its drug can significantly reduce the risk of heart attacks, strokes, and cardiovascular death, the company will experience further appreciation. In the 2023 European Society of Cardiology (ESC) Congress, Novo Nordisk announced the interim results of its phase trial. The results of the STEP HFpEF trial showed that in obese patients with heart failure with preserved ejection fraction (HFpEF), the use of Wegovy improved the severity of heart failure and reduced heart failure hospitalization rates compared to placebo. Wegovy showed comparable efficacy to approved heart failure-specific drugs.

Based on the main results of the STEP HFpEF and SELECT trials, Wegovy can reduce major adverse cardiovascular events (MACE) in patients diagnosed with cardiovascular disease by 20%. This indicates that the use of Wegovy can reduce the risk of cardiovascular disease, highlighting the need for a shift in the treatment paradigm for cardiovascular disease with a focus on obesity treatment. The positive results of the Wegovy SELECT trial will lead to a paradigm shift in cardiology practice, where obesity treatment should become central to future treatment strategies.

Overall, the STEP HFpEF data itself supports the use of Wegovy in HFpEF patients, who constitute 1-2% of the total population with obesity. Further research data from the SELECT trial will be presented at the American Heart Association (AHA) conference in November 2023, which could result in a transformation of the treatment paradigm for cardiovascular disease, further supporting Novo Nordisk's strong growth.

In December 2022, the eligible population for Wegovy expanded to adolescents aged 12 and above, making it the first and only once-weekly prescribed anti-obesity drug for teenagers (based on STEP-TEENS). This further demonstrates the potential and effectiveness of this medication in treating obesity.

The efficacy of Mounjaro/Wegovy typically lasts for two years. After using Wegovy and Mounjaro, patients generally experience sustained weight loss for two years. If the weight loss is not sustained, combination therapy (Wegovy plus phentermine) should be considered.

Due to the possibility of weight regain upon discontinuation and the potential dependency of weight-loss drugs, the duration of drug use is indirectly extended. Novo Nordisk has not disclosed the average duration of medication for drugs like Wegovy. However, according to The Economist, those who start taking new drugs are likely to become dependent on them for life. If the medication is stopped, weight regain occurs, similar to most conventional dieting methods. In the first year after discontinuing the 2.4 mg dose of semaglutide, people's weight tends to recover to two-thirds of the previous weight. Some individuals may even gain more weight than before starting the medication. The necessity of continued injections has been recognized by pharmaceutical companies, but due to a lack of data on the long-term effects of lifelong medication, doctors are more cautious. The draft National Guideline in the UK states that the duration of semaglutide treatment for weight loss should not exceed two years.

Patients are not only interested in regaining lost weight but also value the broader health benefits. If efficacy data supports cardiovascular benefits for patients, doctors would recommend long-term use of these medications. It is expected that the proportion of patients continuing treatment will increase by over 50%. Most patients will adhere to the treatment for at least one year, while some may transition to intermittent use once weight loss stabilizes.

In the United States, Wegovy costs approximately $1,300 per month, and Ozempic costs around $900. Based on these prices, lifelong prescriptions may seem expensive. However, the involvement of medical insurance will improve this situation, especially considering their impact on improving cardiovascular disease (CVD). Prescribers and payers will favor weight loss medications to reduce complications and lower broader healthcare costs. Additionally, J.P. Morgan predicts that pricing for obesity (and T2D) will decrease annually, reaching a net price of about $4,000 per year by 2030.

The market is expected to expand the prospects for GLP-1 in multiple indications.The development of global GLP-1 analogs has gradually expanded from type 2 diabetes and obesity to other fields, such as non-alcoholic fatty liver disease, Parkinson's disease, and improvement of diabetes complications. According to Novo Nordisk's 2022 financial report presentation materials, in addition to diabetes and obesity indications, semaglutide is also positioned for indications in cardiovascular diseases, non-alcoholic fatty liver disease, chronic kidney disease, Alzheimer's disease, and heart failure. These are all areas with enormous clinical potential.

Eli Lilly expects to obtain data on sleep apnea in the first quarter of 2024 and data on high-frequency heart failure in the second quarter of 2024. In addition, GLP-1 analogs are expected to be used for the treatment of chronic kidney failure between the end of 2024 and 2025, and for the treatment of major adverse cardiovascular events (MACE) in 2026/2027.

Multi-target agonists have become a current research hotspot. As of August 2023, several global dual/multi-target agonists have entered the clinical trial stage, mainly focusing on combinations such as GLP1R/GIPR, GLP-1R/GCGR, etc. In the dual-target combinations of GLP-1R/GIPR and GLP-1R/GCGR, companies such as Eli Lilly, AstraZeneca, and Merck have already made strategic arrangements. Multi-target drugs have significant advantages in terms of efficacy and patient compliance.