From early tonics to prescription drugs, the idea of a simple solution for weight loss has never lost its appeal.
Over the last century, pharmaceutical development for obesity has swung between promise and peril, with many treatments pulled from the market due to safety concerns. Yet today, the field is experiencing a new era of innovation, with medications and procedures that not only help with weight but also improve metabolic health.
Each setback and safety scare has shaped stricter standards, sharper oversight, and a more cautious approach to drug design. What has emerged is a generation of therapies that strike a balance between effectiveness and safety, prioritizing patient well-being.
Beginning with Thyroid Extracts
The first widespread pharmacologic treatments for obesity came from thyroid extracts in the late 1800s. Doctors noticed that patients with overactive thyroids tended to be thin, so thyroid hormone was prescribed to accelerate metabolism. While it often produced weight loss, it also caused palpitations, muscle wasting, and sometimes heart failure.1
In the 1930s, a chemical called 2,4-dinitrophenol (DNP) was introduced. While used as an herbicide, photo developer, and in munitions production, a researcher at Stanford realized in 1933 that consuming the substance would also induce weight loss. DNP uncoupled cellular energy production, effectively turning the body into a furnace that burned calories. Rapid weight loss followed – but so did cataracts, dangerous fevers, and deaths. By 1938, DNP was banned for human use by the Federal Food Drug and Cosmetic Act of 1938.2
The Amphetamine Era
Amphetamines were first synthesized in the late 19th century, but their pharmacological potential wasn’t fully appreciated until the 1920s and 1930s. In 1937, doctors discovered that amphetamine sulfate (Benzedrine) could suppress appetite.3 This was a turning point: for the first time, a pill could reliably reduce hunger, making it extremely appealing for both doctors and patients.
By the 1940s and 1950s, amphetamines became a standard prescription for weight loss, often marketed as harmless “pep pills.” They were available not only in medical settings but also in over-the-counter inhalers, fueling widespread use.
By the 1950s and 1960s, amphetamines were being prescribed widely, but their addictive potential and cardiovascular risks became more and more apparent.
The problem was twofold:
1. Amphetamines act on the dopamine and norepinephrine systems, producing euphoria, energy, and decreased appetite. By the 1960s, misuse was rampant, especially in the U.S. and Japan, where “epidemics” of non-medical use emerged.
2. There were cardiovascular and psychiatric risks. Patients developed dependence, insomnia, anxiety, psychosis, and, in some cases, severe cardiovascular complications.
As the dangers became increasingly apparent, regulators put tighter restrictions on prescriptions. By the 1970s, amphetamines had shifted from diet aids to controlled substances.
The Rise and Fall of Fen-Phen
After the amphetamine era, pharmaceutical companies sought safer appetite suppressants. One avenue was fenfluramine, a drug that increased serotonin release and dampened appetite. Approved in 1973, fenfluramine was modestly effective but limited by drowsiness and other side effects.
In the 1980s and 1990s, researchers found that combining fenfluramine with phentermine (a mild stimulant approved in 1959) produced greater weight loss with fewer complaints of jitteriness. This “Fen-Phen” duo took off in the mid-1990s, helped by aggressive promotion and patient demand. By some estimates, over 18 million prescriptions were written in the U.S. alone.
Initially hailed as a breakthrough, Fen-Phen became emblematic of how fast adoption can outpace safety data. Reports began surfacing in 1997 of women developing pulmonary hypertension and, more alarmingly, valvular heart disease – a rare but devastating condition.4-5 The proposed mechanism was stimulation of serotonin receptors on heart valves, leading to abnormal growth and scarring.
The FDA quickly intervened. By September 1997, fenfluramine and its isomer dexfenfluramine were withdrawn from the market, cementing a notorious chapter in weight loss drug history and leaving only phentermine (which is still prescribed today for short-term use as an appetite suppressant). Thousands of patients filed lawsuits, resulting in one of the largest pharmaceutical settlements in history.
The Fen-Phen episode was a watershed moment:
- It reinforced public skepticism of diet drugs.
- It made regulators far more cautious, setting stricter safety requirements for all future obesity medications.
- It highlighted how complex appetite regulation is, tied not only to the brain but also to systems like cardiovascular physiology.
A Safer Approach
After the Fen-Phen disaster, regulators and physicians were wary of any appetite-suppressing drugs. The search shifted from central nervous system stimulants to mechanistically targeted approaches. Enter orlistat, approved by the FDA in 1999 (Xenical) and later as an over-the-counter lower-dose formulation (Alli) in 2007.
Orlistat works differently from its predecessors: rather than suppressing appetite, it blocks intestinal lipases, the enzymes responsible for breaking down dietary fat. It allows a portion of ingested fat to pass through the gut unabsorbed, reducing caloric intake. This non-systemic mechanism was appealing because it avoided the cardiovascular and psychiatric risks associated with stimulants.6
Orlistat marked a turning point in obesity pharmacotherapy:
- Safety-first innovation: Regulators now demanded more precise mechanisms of action and long-term safety data.
- Shift toward lifestyle integration: Weight loss drugs were no longer seen as stand-alone solutions; success depended on diet and exercise.
Prioritizing safety, metabolic benefits, and long-term use demonstrated that even modest interventions could yield meaningful health benefits. With tighter oversight and a deeper understanding of how lifestyle shapes metabolic health, the foundation was set for a new generation of therapies, including today’s GLP-1 receptor agonists (GLP-1 RAs).
GLP-1 RAs
GLP-1 medications were originally developed to treat type 2 diabetes because they help lower blood sugar by stimulating insulin release in response to glucose. They also slow gastric emptying to keep blood sugar levels steady after meals.
In both clinical trials and real-world use, researchers noticed an added benefit: weight loss. This effect comes from the drugs’ ability to suppress appetite and increase feelings of fullness, both by slowing stomach emptying and by sending signals to the brain that help regulate hunger.
Liraglutide (Saxenda, Victoza) was one of the first GLP-1 RAs approved specifically for weight management. In clinical trials, obese adults with at least one weight-related health issue lost around 8% of their starting weight over the course of a year, compared with just 2-3% in those on placebo. Participants also saw improvements in blood pressure, cholesterol, and markers of inflammation.7
Semaglutide (Ozempic, Wegovy), a once-weekly GLP-1 RA, has also produced remarkable results in non-surgical weight management. Adults taking a 2.4 mg dose in one study lost 10-20% of their body weight in addition to improvements in blood sugar, cardiovascular risk factors, and overall quality of life.8
More recently, dual- and triple-agonist therapies like tirzepatide (Zepbound, Mounjaro) have emerged, offering a stronger approach to weight and metabolic management. Unlike single-hormone GLP-1 therapies, tirzepatide targets multiple hormones that help control appetite and blood sugar, giving it a broader effect on metabolism. Adults participating in tirzepatide studies lost at least 20% of their body weight over 72 weeks, along with meaningful improvements in blood sugar, cholesterol, and other metabolic markers.9
Tried and True
While medications from orlistat to the latest GLP-1 RAs have transformed treatments available for obesity, bariatric surgery is still the most reliable path to substantial and sustained weight loss. Procedures such as gastric bypass, sleeve gastrectomy, and adjustable gastric banding physically restrict the stomach’s capacity and alter gut hormones, producing dramatic effects on appetite, satiety, and metabolism. Many patients experience significant weight loss within the first year, often exceeding what is possible with even the most advanced medications.
Bariatric surgery also delivers significant improvements in comorbid conditions. Patients frequently see remission of type 2 diabetes, reductions in blood pressure and cholesterol levels, and improvements in sleep apnea, joint pain, and overall physical stamina. Unlike drugs that have to be taken continuously to maintain results, surgical interventions provide long-term metabolic benefits and can fundamentally reset the body’s energy balance for good.
If you’re considering taking the next step toward lasting weight loss and improved health, we’re here to guide you every step of the way. With a multidisciplinary team of experienced surgeons, VIPSurg provides comprehensive care from preoperative assessment to postoperative support, ensuring that patients achieve sustainable results safely. Schedule a consultation to see if surgery, medication, or a combination of both is right for you.
- Bray, George A., and Jonathan Q. Purnell. “An Historical Review of Steps and Missteps in the Discovery of Anti-Obesity Drugs.” PubMed, MDText.com, Inc., 10 July 2022, www.ncbi.nlm.nih.gov/books/NBK581942/.
- Grundlingh, J., Dargan, P. I., El-Zanfaly, M., & Wood, D. M. (2011). 2,4-dinitrophenol (DNP): a weight loss agent with significant acute toxicity and risk of death. Journal of medical toxicology : official journal of the American College of Medical Toxicology, 7(3), 205–212. https://doi.org/10.1007/s13181-011-0162-6.
- Rasmussen N. (2008). America’s first amphetamine epidemic 1929-1971: a quantitative and qualitative retrospective with implications for the present. American journal of public health, 98(6), 974–985. https://doi.org/10.2105/AJPH.2007.110593.
- Connolly, H. M., Crary, J. L., McGoon, M. D., Hensrud, D. D., Edwards, B. S., Edwards, W. D., & Schaff, H. V. (1997). Valvular heart disease associated with fenfluramine-phentermine. The New England journal of medicine, 337(9), 581–588. https://doi.org/10.1056/NEJM199708283370901.
- Surapaneni, P., Vinales, K. L., Najib, M. Q., & Chaliki, H. P. (2011). Valvular heart disease with the use of fenfluramine-phentermine. Texas Heart Institute journal, 38(5), 581–583. https://pmc.ncbi.nlm.nih.gov/articles/PMC3231534/.
- Bansal, Agam B., et al. “Orlistat.” PubMed, StatPearls Publishing, 14 Feb. 2024, www.ncbi.nlm.nih.gov/books/NBK542202/.
- Pi-Sunyer, Xavier, et al. “A Randomized, Controlled Trial of 3.0 Mg of Liraglutide in Weight Management.” New England Journal of Medicine, vol. 373, no. 1, 2 July 2015, pp. 11–22, www.nejm.org/doi/full/10.1056/NEJMoa1411892, https://doi.org/10.1056/nejmoa1411892.
- Wilding, John P. H., et al. “Once-Weekly Semaglutide in Adults with Overweight or Obesity.” The New England Journal of Medicine, vol. 384, no. 11, 10 Feb. 2021, pp. 989–1002. PubMed, www.nejm.org/doi/full/10.1056/NEJMoa2032183, https://doi.org/10.1056/NEJMoa2032183.
- Jastreboff, Ania M., et al. “Tirzepatide Once Weekly for the Treatment of Obesity.” New England Journal of Medicine, vol. 387, no. 3, 4 June 2022, pp. 205–216, www.nejm.org/doi/full/10.1056/NEJMoa2206038, https://doi.org/10.1056/nejmoa2206038.