New weight-loss drugs have become wildly popular in recent years, but Americans have been seeking to control weight through medication for well over a century. This post, the final installment in our series on weight-loss drugs, continues a historical review that began in our last post and then looks ahead to possible future developments.
The 1990s
In the early 1990s, some doctors began prescribing a combination of fenfluramine and phentermine, known as “fen-phen,” for weight loss. Fenfluramine, sold under the brand names Pondimin and Ponderax, worked by increasing the levels of serotonin, a neurotransmitter, in the brain. Serotonin suppresses appetite, ultimately resulting in weight loss. Phentermine, sold under the brand names Adipex-P, Lomaira, and Suprenza, increases the release of another neurotransmitter, norepinephrine, which signals the body to reduce hunger and increase feelings of fullness.
Both drugs were individually approved by the U.S. Food and Drug Administration (FDA) as anorectic agents, or appetite suppressants, for short-term use to treat obesity — phentermine in 1959 and fenfluramine in 1973 — although the FDA never approved the drugs in combination. By 1996, the total number of fenfluramine and phentermine prescriptions in the United States exceeded 18 million.
In 1997, a study published in the New England Journal of Medicine reported that some patients who had taken fen-phen developed a rare but serious condition called primary pulmonary hypertension (PPH), a type of high blood pressure that affects the arteries in the lungs. Subsequent research linked fenfluramine to an increased risk of heart valve problems — specifically valvular heart disease, a condition that causes the heart valves to become thickened or damaged — particularly when used in combination with phentermine. These findings led to the withdrawal of fenfluramine from the market in 1997. Phentermine, however, remains on the market.
Dexfenfluramine (brand name REDUX), a drug closely related to fenfluramine, was approved by the FDA in 1996. Dexfenfluramine worked by increasing the release of serotonin and inhibiting its reabsorption, leading to increased feelings of fullness and reduced appetite. In 1997, the FDA asked that dexfenfluramine be withdrawn from the market after reports emerged linking it to serious side effects, including heart valve problems and PPH. The manufacturer, Indevus (formerly Interneuron Pharmaceuticals, Inc.), complied.
Sibutramine (brand name Meridia) was approved by the FDA in 1997 for weight loss and maintenance of weight loss. Sibutramine worked by increasing levels of serotonin and norepinephrine in the brain, helping to reduce appetite. However, in 2010, after reviewing data from the Sibutramine Cardiovascular Outcomes Trial (SCOUT) which showed an increased risk of major adverse cardiovascular events, such as non-fatal heart attack and non-fatal stroke, the FDA recommended against the prescribing of Sibutramine, and the drug’s manufacturer agreed to voluntarily stop marketing it in the United States.
In a different approach to weight loss, Proctor & Gamble marketed olestra (brand name Olean) in the 1990s. Olestra was not a medication but a fat substitute used in snack foods, such as potato chips and crackers, to reduce fat calories without sacrificing taste. Olestra works by passing through the digestive system without being absorbed, so, unlike fat, it adds no calories to the diet. However, olestra was later found to have several drawbacks, primarily digestive side effects, such as cramping, gas, and diarrhea, especially when consumed in large amounts. Olestra can also interfere with the absorption of fat-soluble vitamins such as vitamins A, D, E, and K, raising concerns about the potential for nutrient deficiencies in people who consume olestra regularly.
As a result of these findings, the popularity of olestra declined, and many food manufacturers stopped using it in their products. While olestra is still approved for use in the United States, it is no longer widely used in the food industry.
The 2000s
Orlistat was first approved by the FDA for prescription for weight loss in 1999. In 2007, orlistat was approved under the brand name Alli for over-the-counter use. Orlistat works by inhibiting pancreatic lipase, an enzyme that breaks down dietary fats in the intestine. This inhibition reduces the absorption of dietary fats, leading to weight loss. Orlistat is typically used in conjunction with a reduced-calorie diet and an exercise program for the management of obesity.
While orlistat was shown to be effective for weight loss, it was also shown to cause gastrointestinal side effects such as oily spotting, flatulence, and oily stools. Additionally, it may reduce the absorption of fat-soluble vitamins such as vitamins A, D, E, and K. Orlistat is still available in both prescription and over-the-counter forms.
The 2010s to the Present
Lorcaserin (brand name Belviq) was approved by the FDA in 2012, making it the first weight-loss drug approved since orlistat. Lorcaserin works by activating serotonin receptors in the brain, resulting in reduced appetite and feelings of fullness.
Lorcaserin was thought to be a safer alternative to previous weight-loss medications, as it was designed to specifically target serotonin receptors involved in appetite regulation, with less effect on other serotonin receptors that could lead to side effects. However, after the results of a safety clinical trial indicated an increased occurrence of cancer, Lorcaserin was voluntarily withdrawn in 2020.
Qsymia is a combination of two medications, phentermine (the component of “fen-phen” that remained on the market) and topiramate. Topiramate is an anticonvulsant that helps with weight loss by increasing feelings of fullness and reducing food cravings. Qsymia was approved by the FDA in 2012 and is still on the market; it received approval for patients aged 12 years and older in 2022.
Contrave, approved by the FDA in 2014, is a combination of two medications, naltrexone and bupropion. Naltrexone is used to treat alcohol and opioid dependence, while bupropion is an antidepressant and smoking cessation aid. Naltrexone can reduce food cravings by blocking opioid receptors that are involved in the reward pathway associated with food intake, while bupropion can help to reduce appetite and increase energy expenditure. The combination of naltrexone and bupropion works synergistically to reduce appetite and food cravings. Contrave remains an FDA-approved drug for weight management.
Over the past two decades, glucagon-like peptide-1 (GLP-1) receptor agonists have emerged as a promising class of medications for the treatment of obesity. Originally developed for type 2 diabetes management, GLP-1 receptor agonists such as liraglutide and semaglutide were found to also induce weight loss. These drugs, marketed under brand names such as Ozempic and Wegovy, work by mimicking the action of a hormone called GLP-1 which regulates appetite and food intake. We discussed this class of drugs in a previous post, “Weight-Loss Drugs: What’s in Them and How They Work.”
The Future
Novel mechanisms and improved safety are the focus of research for new weight-loss drugs. One significant development is the exploration of combination therapies, e.g., combining GLP-1 receptor agonists with agents that promote muscle growth or mimic multiple hormones involved in appetite regulation. Other research focuses on a different kind of hormone, apelin. BioAge Labs, in collaboration with Chorus (a clinical development organization within Eli Lilly), is exploring a combination of azelaprag (a drug that mimics apelin) with the GLP-1 receptor agonist tirzepatide to enhance the performance of weight-loss drugs. Such advancements could lead to more effective and safer weight-loss medications in the future.
Additionally, efforts are underway to develop oral formulations of GLP-1 receptor agonists, which currently are usually injected, to reduce barriers to uptake and increase acceptability for patients.
The weight-loss drug industry continues to evolve in pursuit of safer and more effective treatment options. However, as we have seen over many decades, the long-term effects of a drug often remain unknown until years after the drug enters the market.
For more, see our other posts in this series:
“Weight-Loss Drugs: What’s in Them and How They Work”
“Weight-Loss Drugs: What They Mean for Children With Obesity”
“Weight-Loss Drugs: Cost and Cost-Effectiveness”
“Weight-Loss Drugs: Other Key Considerations”
“Weight-Loss Drugs: A Historical Review, Part 1”
