Many of us, myself included, have embarked on weight loss journeys at different points in our lives. And if I’m being honest, most attempts don’t lead to much—if any—lasting change. It’s a bit of a downer, really. However, a glimmer of hope appeared in recent years with semaglutide, the key ingredient in Ozempic and Wegovy. Semaglutide functions like GLP-1, a hormone that plays a role in managing appetite and insulin levels. Newer GLP-1 medications—and even some that focus on multiple hormones—are proving significantly more effective for weight loss than traditional methods like diet and exercise, not to mention other treatments outside of top-tier bariatric surgeries.
Sure, GLP-1 medications come with their own drawbacks, including side effects and the reality that many will regain weight if they discontinue use. Still, they have marked the beginning of a fresh chapter in obesity treatment, one that’s actually reflecting a decline in obesity rates in the U.S. and other places.
With Wegovy approaching its five-year anniversary of approval, I thought it would be interesting to revisit some past obesity treatments that ultimately didn’t pan out and explore why they failed.
2,4-Dinitrophenol (DNP)
2,4-Dinitrophenol, or DNP, has had quite the history. Initially used in dyes and explosives, scientists in the 1930s discovered its potential for rapid weight loss, with some reporting losses of up to three pounds a week. It does this by interfering with how mitochondria produce energy, leading to increased metabolic rates as the energy is dissipated as heat instead of stored in the body.
That said, using too much DNP can lead to severe overheating—quite literally. Users might also face other severe side effects like cataracts or kidney failure. Compounding this is DNP’s narrow therapeutic window, where the difference between a “safe” amount and a dangerous dose is quite small.
After these side effects became known, countries like the U.S. quickly banned DNP as a weight loss solution. Yet, it’s still relatively easy to obtain today. Some people, especially bodybuilders, continue to take significant risks with it, and tragically, some have even paid the ultimate price. Interestingly, some researchers are looking into whether DNP’s mechanisms could be adapted safely for obesity treatment.
Lap Bands
Even amidst the rise of GLP-1 treatments, various types of bariatric surgery remain effective for obesity, especially in severe cases. While these surgeries generally have a good safety record, they can be expensive and lead to permanent changes. One alternative was the lap band, designed to address some of these issues.
This minimally invasive procedure involves placing an adjustable band around the stomach to reduce its size, allowing individuals to feel full with less food. Early studies showed promising results, and the lap band was quite popular in the late 2000s.
Over time, however, complications began to emerge. Many users suffered issues like infections and the band loosening over time, often resulting in weight regain or the need for more surgeries. Concurrently, doctors made strides in enhancing the safety and effectiveness of other surgeries, like the sleeve gastrectomy.
While the lap band was never officially banned, its popularity declined steeply by the late 2010s, and many current bariatric centers have stopped offering it altogether.
Fen-phen
Fen-phen is a combination of fenfluramine and phentermine.
Both of these drugs help curb appetite but do so in different ways. Initially approved as short-term aids for obesity, they had only modest effects until the late 1970s when a pharmacologist proposed that mixing them could yield better results. By the 1990s, fen-phen had become hugely popular, with millions of prescriptions written annually.
Unfortunately, it was widely prescribed off-label without thorough testing, unlike GLP-1s. Reports of serious complications followed, including heightened risks for heart valve disease and pulmonary hypertension. By late 1997, the FDA called for fenfluramine and its related drug, dexfenfluramine, to be removed from the market, effectively ending the fen-phen era and costing its manufacturer billions in legal challenges.
The serious health issues were predominantly linked to fenfluramine. Meanwhile, phentermine is still prescribed occasionally, often alongside topiramate, which can provide modest weight loss without the severe risks. Fenfluramine has since found a new purpose in treating certain types of seizures, but with stark warnings about its cardiovascular risks.
Lorcaserin
Lorcaserin was noteworthy when it received FDA approval in 2012, being the first new drug for obesity in over a decade.
However, it only offered modest weight loss, possibly around six pounds in 12 weeks. More concerning was the potential cancer risk it presented. A subsequent FDA investigation revealed that 7.7% of lorcaserin users developed cancer within five years, compared to 7.1% of those taking a placebo.
In 2020, the FDA requested the removal of lorcaserin from the market, which the manufacturer complied with. A year later, Wegovy was approved. Ironically, some studies have suggested that GLP-1 treatments may even reduce the overall risk of cancer.
Rainbow Pills
Fen-phen wasn’t the first attempt at weight loss through multi-drug combinations; that title belongs to “rainbow pills,” named for their vibrant colors.
These pills peaked in popularity during the 1940s and 1950s when companies mixed various drugs believed to aid weight loss, including amphetamines and diuretics, paired with substances to negate side effects, like barbiturates for anxiety. Obviously, such combinations were risky, especially since dosages varied widely from pill to pill. There were at least sixty deaths linked to rainbow pills, leading to FDA intervention and a ban by the late 1960s.
Rainbow pills remained somewhat popular elsewhere, and some researchers argue that many current weight-loss supplements may be revamped versions of these previous concoctions. These supplements often lack regulation compared to prescribed drugs and could be misleadingly marketed or laced with the same types of ingredients as rainbow pills.
Speaking of supplements…
Ephedra
Ephedra is the name of a shrub genus, but it’s most often talked about in relation to the stimulant ephedrine.
In the 1990s, Ephedra became widely used for weight loss and performance enhancement, often combined with caffeine, which some studies suggested could amplify its effects. However, as its popularity grew, so did reports of negative events—high blood pressure, stroke, and even psychosis were among them.
The final blow for Ephedra came when MLB pitcher Steve Bechler died from heat stroke during spring training in 2023, with an autopsy linking his death to Ephedra use. Following an investigation, the FDA shocking step of completely banning Ephedra supplements with ephedrine followed. Before the ban, Ephedra was linked to at least 155 deaths.
Perhaps the saddest part of this story is that Ephedra wasn’t even all that effective. Even combined with caffeine, it only helped individuals lose a modest one to two pounds more per month on average.
