In June 2021, the US FDA approved Novo Nordisk's semaglutide injection Wegovy? for the treatment of obesity (BMI ≥ 30 kg/m2) or overweight (BMI ≥ 27 kg/m2 with at least one obesity-related disease). The drug immediately ignited enthusiasm in the weight loss market. According to Novo Nordisk's quarterly reports, in the first quarter of 2025, the sales of semaglutide's three products reached 55.776 billion DKK (approximately 8.411 billion USD), with Wegovy? accounting for 17.36 billion DKK (approximately 2.618 billion USD). We also know that many versions of semaglutide, such as Ozempic? (designed for diabetes), have been used off-label for weight loss, meaning the actual sales share from weight loss is likely even higher. This reminds me of various weight loss drugs in pharmaceutical history. In an age where being slim is considered beautiful, once a drug is associated with weight loss, it becomes the focus of daily discussion. Nowadays, weight loss is no longer just about "health" but has become a topic that transcends age, gender, and class. However, safety has always been an "ominous cloud" hovering over weight loss medications. History has proven that many weight loss drugs on the market were eventually withdrawn due to severe adverse reactions.
The first weight loss drug we will discuss is Fenfluramine, marketed as Pondimin?. The story of this drug dates back to the 1960s. Due to its ability to suppress appetite and reduce weight, especially when combined with phentermine (Fastin?) in the "Fen-Phen" combination, it became extremely popular. The drug works by increasing serotonin levels (a neurotransmitter that regulates mood, appetite, and other functions) while also having a mild norepinephrine-releasing function, which enhances satiety and reduces appetite. It was first marketed in France in 1963, and from 1963 to 1996, approximately 50 million Europeans used it for weight loss. In 1973, the US FDA approved its sale, and statistics show that between 1996 and 1998, about 5 million Americans used Fenfluramine either alone or in combination with phentermine for weight loss, making the manufacturer, A.H. ROBINS, a fortune.
However, disaster struck in the early 1990s. French researchers reported that a small number of patients developed primary pulmonary hypertension and breathing difficulties linked to Fenfluramine. In 1995, the FDA reviewed the approval documents for dexfenfluramine (the active right-handed isomer of Fenfluramine) and found cases of pulmonary hypertension in European clinical trials. Although initially skeptical, the FDA approved dexfenfluramine in 1996 by a narrow vote of 6:5. In 1997, two articles were published in the New England Journal of Medicine, one of which focused on 24 cases of heart valve disease related to the "Fen-Phen" combination, while the other reported that short-term use of dexfenfluramine and Fenfluramine caused fatal pulmonary hypertension. Faced with substantial evidence, the FDA decided to withdraw approval for Fenfluramine and dexfenfluramine in 1997, leading to the dissolution of the once-popular "Fen-Phen" combination.
Phenylpropanolamine, a sympathomimetic drug, was first synthesized around 1910 and widely used in the 1930s as a decongestant and weight loss medication. It does not directly activate adrenergic receptors (its affinity is very weak), but rather induces the release of norepinephrine, which activates these receptors, constricting nasal mucosal blood vessels, reducing congestion, and suppressing appetite for weight loss. However, clinical practice revealed several adverse effects, including high blood pressure, rapid heart rate, intracranial hemorrhage, and even stroke. In November 2000, the US FDA issued a warning based on a report from Yale University scientists that Phenylpropanolamine caused an increased risk of hemorrhagic stroke in patients aged 18-49. The FDA planned to reclassify PPA-containing drugs as "non-legend" (not considered safe or effective) and remove it from the prescription drug list. With the growing negative reputation, many subsequent cold medications marketed themselves as "PPA-free." Today, PPA is banned in most countries, with only a few continuing to sell it.
Sibutramine was developed by the British Boots company in 1988. It is a serotonin-norepinephrine reuptake inhibitor (SNRI) that reduces the reuptake of norepinephrine (73%), serotonin (54%), and dopamine (16%) in the body, thereby increasing the concentration of these substances in the synaptic cleft and enhancing satiety. In 1997, the US FDA approved its use for the treatment of obesity (BMI ≥ 30 kg/m2 or BMI ≥ 27 kg/m2 with cardiovascular risk factors). However, starting in 2002, studies began to report serious side effects associated with Sibutramine, including sudden death, heart failure, renal failure, and gastrointestinal issues. The most famous study was the "Sibutramine Cardiovascular Outcomes" (SCOUT) trial, which enrolled 10,742 patients. The results showed that the relative risk (RR) for primary clinical outcomes (including non-fatal heart attacks, non-fatal strokes, cardiac arrest, and cardiovascular death) in the Sibutramine group was 1.16. Based on these findings, the European EMA recommended halting Sibutramine sales in 2010. The US FDA followed suit, advising against its prescription and requesting Abbott to withdraw it from the market. Abbott complied, and Sibutramine was removed from the US market.
Rimonabant is a type 1 cannabinoid receptor (CB1) antagonist that works by inhibiting the endocannabinoid system to suppress appetite and reduce food intake. Developed by Sanofi-Aventis, it was approved for use in the EU in June 2006 for obesity (BMI ≥ 30 kg/m2 or BMI ≥ 27 kg/m2 with related diseases such as diabetes and dyslipidemia). However, it was never approved by the US FDA, as the manufacturer failed to prove its safety. Clinical trials revealed that about 10% of patients taking Rimonabant developed mood changes or depression, and 1% experienced suicidal thoughts. A large clinical trial (CRESCENDO) involving 18,000 participants across 42 countries found that 32% of Rimonabant users had psychiatric side effects such as anxiety, depression, and insomnia. In October 2008, the European EMA recommended stopping Rimonabant use, and it was banned in several countries, including Brazil and India, by 2009.
Lorcaserin, developed by Arena Pharmaceuticals and marketed as Belviq?, works by activating the 5-HT2c receptor in the hypothalamus, promoting the release of pro-opiomelanocortin (POMC) to increase satiety. Clinical trial data shows that after nearly a year of treatment (along with calorie management and exercise), patients lost an average of 3–3.7% of their body weight. In 2012, the US FDA approved it for the treatment of obesity (BMI ≥ 30 kg/m2 or BMI ≥ 27 kg/m2 with related diseases such as diabetes and hypertension). However, the FDA required post-market cardiovascular safety trials. After five years, the "CAMELLIA-TIMI 61" trial, which included about 12,000 patients, showed no significant difference in major cardiovascular events between the treatment and control groups, but it did reveal an increased cancer risk for those taking Lorcaserin. In February 2020, the FDA asked the manufacturer to voluntarily withdraw the drug from the market.
In addition to the five drugs mentioned above, there are other weight loss drugs such as 2,4-dinitrophenol (DNP), methamphetamine (the active ingredient in crystal meth), and amphetamines. These products pose significant harm to the body and can even cause death. Weight loss should be approached scientifically, and medication should be used with caution!
[2]. W. Philip T. James, "The SCOUT study: risk-benefit profile of sibutramine in overweight high-risk cardiovascular patients", European Heart Journal Supplements, Volume 7, Issue suppl_L, November 2005, Pages L44–L48
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