The Dark Side of Slimming Down: A 100-Year Journey of Weight Loss Drugs

By: Noah W Chung | PharmD

Weight loss drugs have long occupied a complicated space in medicine—offering hope for those struggling with obesity while simultaneously sparking controversy due to side effects, misuse, and inconsistent results. From dubious potions of the early 20th century to the scientifically engineered GLP-1 receptor agonists of today, the journey of pharmacological weight management reflects both scientific progress and shifting societal attitudes toward body image, health, and responsibility.

This article explores the historical trajectory of weight loss drugs, examining their scientific basis, regulatory battles, public reception, and what lies ahead for pharmacotherapy in obesity management.

Early 20th Century: The Rise of Stimulants and Dangerous Experiments

In the 1920s, thyroid hormone extracts were prescribed to boost metabolism and aid in weight loss, but their use led to severe side effects like heart palpitations and muscle wasting. Around 1933, 2,4-Dinitrophenol (DNP) entered the market, increasing metabolic rate by uncoupling oxidative phosphorylation in mitochondria. It caused dramatic weight loss—but also fatal hyperthermia, cataracts, and neuropathy, leading the FDA to ban it in 1938.

1940s–1960s: The Amphetamine Era

Amphetamines such as Benzedrine and Dexedrine were prescribed for obesity starting in the 1940s. They were highly effective appetite suppressants but carried serious risks of addiction, hypertension, and psychosis. The 1965 Drug Abuse Control Amendments introduced federal control due to widespread misuse.

1970s–1980s: Combination Therapies and Fen-Phen

The combination of fenfluramine and phentermine—“fen-phen”—was a popular treatment by the 1990s. It showed promising weight loss results but soon led to reports of cardiac valvulopathy and pulmonary hypertension.

In 1997, the FDA pulled fenfluramine and dexfenfluramine from the market. More than 50,000 lawsuits followed, and manufacturer Wyeth paid over $13 billion in settlements.

1999–2009: Lean Years for Innovation

Approved in 1999, orlistat was one of the few remaining FDA-approved weight loss medications. It inhibits pancreatic lipase to reduce fat absorption. Marketed as Xenical (prescription) and Alli (OTC), its side effects—especially gastrointestinal—limited its popularity.

Rimonabant, approved in Europe in 2006, blocked CB1 cannabinoid receptors to reduce appetite. However, it was never approved in the U.S. and was withdrawn by the EMA in 2008 due to increased risk of depression and suicidal ideation.

2010s: Renewed Approvals Amid Caution

Lorcaserin, approved in 2012, worked via serotonin 2C receptor activation. It was moderately effective but withdrawn by the FDA in 2020 after a randomized controlled trial showed increased cancer risk.

Qsymia, a combination of phentermine and topiramate, was approved in 2012. It showed robust weight loss but raised concerns due to teratogenic effects and cognitive side effects like confusion and memory loss.

Contrave (bupropion + naltrexone), approved in 2014, worked via appetite and reward pathways. It demonstrated moderate effectiveness but came with warnings for seizures and psychiatric effects.

Saxenda (Liraglutide)

Approved in 2014, Saxenda was the first GLP-1 receptor agonist approved for obesity. It produced 5–10% average weight loss and demonstrated cardiovascular safety. It laid the foundation for the next generation of drugs.

2020s: GLP-1 Agonists and the New Weight Loss Frontier

Semaglutide was approved in 2021 as Wegovy for weight management. Clinical trials showed average 15% body weight reduction. As a once-weekly injection, it revolutionized obesity pharmacotherapy.

Tirzepatide, approved in 2023, is a dual GLP-1 and GIP receptor agonist. Trials like SURMOUNT-1 reported up to 22.5% weight loss, rivaling bariatric surgery.

Cost, Access, and Ethical Concerns

Despite their efficacy, these drugs are expensive—$900 to $1,400/month in the U.S.—and are not consistently covered by insurance. Critics warn of health disparities, as those most in need often cannot afford them.

Moreover, rampant off-label use of Ozempic for cosmetic purposes has strained supply and sparked backlash from the diabetic community.

Cultural Shifts and Changing Attitudes

The recent wave of effective medications has also transformed public perception. Obesity is increasingly seen as a chronic metabolic disorder, not simply a failure of willpower. Still, stigma persists, especially when drugs are used for aesthetic weight loss.

Regulatory Evolution

The FDA's approach has matured, now demanding long-term cardiovascular outcome trials and real-world safety data before or soon after approval. This cautious but supportive regulatory environment has allowed more innovation in the past 5 years than in the previous 20.

The Future of Weight Loss Drugs

Pipeline drugs include triple agonists targeting GLP-1, GIP, and glucagon. Amylin analogs like cagrilintide, when combined with semaglutide, may further enhance weight loss.

Several companies are racing to develop oral GLP-1 receptor agonists to improve compliance and expand access. Genetic testing and personalized obesity profiles may guide drug selection in the future, aligning pharmacotherapy with a patient's unique metabolic and behavioral phenotype.

Conclusion

The history of weight loss drugs reflects a century-long interplay between science, society, and safety. From DNP’s toxicity to the life-changing potential of tirzepatide, each era has left an indelible mark on public health and clinical practice.

The emergence of highly effective agents like Wegovy and Zepbound represents a medical revolution. But challenges in accessibility, affordability, and long-term safety remain.

If the past teaches anything, it's that progress and caution must go hand in hand. The future of obesity treatment is promising—but it must be inclusive, ethical, and scientifically grounded.

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