The Evolution of Obesity Drugs: Lessons from a Century of Failures and the GLP-1 Breakthrough

Image Credit: Adobe Stock Images/Kassandra. GLP-1 receptor agonists have been found to deliver bariatric surgery-level results, with durable benefits and manageable risks.

For much of the twentieth century, obesity was dismissed as a lifestyle issue rather than a chronic disease. Patients were told to eat less and exercise more.

Insurers declined coverage for obesity treatments, writing them off as “cosmetic.” As a result, pharmaceutical research into obesity drugs was underfunded, underappreciated, and often doomed.

When drugs did emerge, the story was predictable: an early wave of excitement followed by disappointment, safety scandals, or regulatory withdrawal. By the late 1990s, obesity pharmacotherapy had earned the reputation of a graveyard for pharmaceutical innovation.

That reputation is now changing. The arrival of GLP-1 receptor agonists and dual agonists has delivered unprecedented efficacy, reframed obesity as a chronic disease, and sparked an industry gold rush.

But to understand this moment, it is important to trace the evolution of obesity drugs, why most failed, and what lessons the industry must carry forward.

Dangerous Beginnings: The 1930s and 1940s

The first widely used obesity drug was 2,4-dinitrophenol (DNP), introduced in 1933. Borrowed from munitions manufacturing, it boosted metabolism by forcing the body to waste energy as heat.

Weight loss was rapid but often fatal. Reports of cataracts, hyperthermia, and deaths mounted, and by 1938, the FDA banned it as “extremely dangerous.”

In the 1940s, amphetamines became the weight-loss drug of choice. Sold under names such as benzedrine, they suppressed appetite and elevated mood.

But their addictive potential and cardiovascular risks quickly became apparent. By the late 1950s, regulators had restricted their use.

The pattern was set: short-term results overshadowed by long-term harm.

The Cocktail Era of the 1950s and 1960s

The next two decades were marked by experimentation and overreach. Methamphetamine was approved in 1947 for obesity but soon proved even more addictive than standard amphetamines. Phentermine, introduced in 1961, was safer and survives today for short-term use.

The most notorious innovation of this era was the “rainbow pill”—capsules combining amphetamines, thyroid hormone, diuretics, and laxatives. Marketed as powerful weight-loss cocktails, they caused arrhythmias, strokes, and organ failure. By 1968, regulators banned them outright.

This period demonstrated a reckless optimism that pharmacology could “cure” obesity, often without scientific rigor or safety oversight.

Hard Lessons of the 1970s and 1980s

In the early 1970s, aminorex appeared in Europe, only to be withdrawn within a year when linked to pulmonary hypertension. In the United States, Obetrol—a mix of amphetamine salts—was briefly marketed for weight loss before being repurposed as Adderall for ADHD.

By the late 1970s, the limitations of stimulant-based drugs were undeniable. Addiction, psychiatric side effects, and cardiovascular damage overshadowed their modest benefits. Still, the unmet need persisted, ensuring that the search for alternatives continued.

Fen-Phen: Promise and Peril in the 1990s

The 1990s brought what seemed to be a breakthrough: the combination of fenfluramine and phentermine, known as Fen-Phen. Prescriptions soared to more than 18 million annually. Patients lost substantial weight, and for a moment, the obesity drug market appeared to have arrived.

Then the nightmare began. Reports of valvular heart disease and pulmonary hypertension surfaced, ultimately linked to fenfluramine’s serotonergic effects on heart valves.

In 1997, the FDA withdrew fenfluramine, unleashing one of the largest pharmaceutical liability cases in history. Manufacturers paid billions in settlements, and confidence in the category evaporated.

Fen-Phen’s collapse hardened regulatory caution and deepened payer skepticism.

Familiar Failures: The 1990s and 2000s

After Fen-Phen, the industry tried new approaches, with mixed results. Ephedra, a stimulant sold in dietary supplements, became wildly popular until it was banned in 2004 for causing heart attacks and strokes.

Sibutramine, approved in 1997, altered serotonin and norepinephrine levels to suppress appetite. After more than a decade on the market, long-term studies revealed increased risk of heart attack and stroke, leading to its global withdrawal in 2010.

Orlistat, approved in 1999, avoided central nervous system stimulation by blocking fat absorption in the gut. It was safe enough to survive, but its notorious gastrointestinal side effects—oily stools and fecal urgency—limited adherence.

Rimonabant, a cannabinoid receptor blocker approved in Europe in 2006, was hailed as novel but caused depression and suicidality. It was withdrawn in 2008 and never approved in the United States.

This period reinforced the core challenges: drugs either proved unsafe or underwhelming, and insurers rarely paid for them.

Incremental Progress: The 2010s

The 2010s brought incremental innovation, but not without setbacks.

Lorcaserin, a serotonin 2C agonist approved in 2012, was initially considered safe. But in 2020, the FDA requested its withdrawal after long-term studies showed increased cancer risk.

More important was liraglutide, marketed as Saxenda, the first GLP-1 receptor agonist approved for obesity. Patients lost 5%–10% of their body weight—an improvement over earlier drugs.

But liraglutide required daily injections and cost more than $1,000 a month. With payers labeling obesity a “lifestyle condition,” coverage was sparse and uptake limited. Even as mechanisms improved, social and economic barriers continued to block widespread adoption.

Why So Many Obesity Drugs Failed

The repeated failures of obesity drugs can be distilled into five themes.

• Cardiovascular toxicity: From amphetamines to sibutramine, many drugs raised blood pressure, triggered arrhythmias, or increased stroke risk.
• Psychiatric complications: Rimonabant and stimulants produced depression, anxiety, or addiction.
• Organ toxicity: Fenfluramine damaged heart valves; DNP caused hyperthermia; aminorex led to pulmonary hypertension.
• Marginal efficacy: Even safer drugs such as orlistat achieved only modest weight loss, disappointing patients.
• Market barriers: Stigma and payer resistance meant that even effective drugs often failed commercially.

This combination of biological complexity and structural resistance explains why the field stagnated for decades.

The GLP-1 Breakthrough: A New Era in the 2020s

Everything shifted in the 2020s with the arrival of modern incretin therapies.

In 2021, semaglutide was approved as Wegovy.

Clinical trials showed average weight loss of 15%–17%, roughly double that of previous drugs. Patients also saw improvements in blood glucose, blood pressure, and cholesterol.

In 2023, tirzepatide (Zepbound), a dual GLP-1/GIP agonist, raised the bar even higher, delivering weight loss of 20%–22%, which is comparable to bariatric surgery outcomes.

These therapies succeeded where others had failed. They offered efficacy that patients and clinicians could not ignore, meaningful cardiometabolic benefits, and a safety profile dominated by manageable gastrointestinal side effects rather than catastrophic risks.

Just as important, their arrival coincided with a cultural shift: obesity was increasingly recognized as a chronic disease rather than a personal failing.

Demand has been explosive, with Novo Nordisk and Eli Lilly struggling to meet it. While payer coverage remains uneven, the sheer scale of efficacy has begun to reshape reimbursement debates.

Obesity drugs are no longer on the fringe; they are central to the future of chronic disease management.

Lessons for Pharma Executives

For pharmaceutical leaders, the evolution of obesity drugs carries important lessons.

• Safety vigilance is non-negotiable. The legacies of Fen-Phen, sibutramine, and rimonabant show how quickly trust evaporates when safety issues emerge. Long-term monitoring and transparent communication will be critical to sustaining confidence in GLP-1s and their successors.
• Payer partnerships must come early. For decades, the biggest barrier was not just biology but reimbursement. Even liraglutide stumbled because coverage was minimal. The future of GLP-1s will hinge on demonstrating downstream cost savings—fewer heart attacks, fewer diabetes complications—to justify broad access.
• Narratives matter. Obesity’s reclassification as a chronic disease has been pivotal. Pharma has a role to play in reinforcing that message to policymakers, clinicians, and the public, ensuring that obesity care is seen as essential rather than elective.
• Access and equity are the next frontier. Demand already outstrips supply, and costs remain prohibitive for many. Companies that solve for manufacturing scale, equitable distribution, and creative pricing models will not only expand the market but also build durable reputational capital.

Conclusion

The history of obesity drugs is one of persistence against long odds. From the reckless use of DNP in the 1930s to the Fen-Phen disaster of the 1990s, most therapies failed because they harmed patients or did too little. Structural barriers such as stigma and lack of coverage further limited progress.

GLP-1 receptor agonists have changed that equation. For the first time, pharmacotherapy can deliver bariatric surgery-level results, with durable benefits and manageable risks. The opportunity is enormous, but so are the responsibilities.

For pharmaceutical executives, the lesson is clear: success in obesity will depend not only on science but also on vigilance, payer alignment, cultural reframing, and equitable access.

After a century of disappointment, the category has finally come of age. Whether the industry seizes this moment to deliver lasting public health impact will define the next chapter of this extraordinary story.

About the Author

Dr. Thani Jambulingam is a professor in food, pharma and healthcare at Erivan K. Haub School of Business, Saint Joseph’s University, Philadelphia. He is a pharma and healthcare strategist and contributing writer to Pharmaceutical Executive. Their work focuses on the intersection of emerging technologies, supply chain, and commercial strategy.