Before the advent of GLP-1 agonists, the pharmacological treatment of obesity was marked by a succession of failures and health scandals. From the amphetamines of the 1950s to Mediator, Fen-Phen, and rimonabant, we look back at a tumultuous history that explains why GLP-1s represent a true therapeutic breakthrough.
The Dark Years: Amphetamines and Derivatives (1950-1990)
The first anti-obesity treatments were based on amphetamines and their derivatives, central nervous system stimulants that suppressed appetite by increasing norepinephrine and dopamine levels in the brain.
- Amphetamine (Benzedrine): Used since the 1930s, it caused dependence, insomnia, tachycardia, and psychiatric disorders. Withdrawn from obesity indication in the 1970s.
- Phentermine: An amphetamine derivative, still available in the United States but banned in Europe since the 2000s. Modest efficacy (-5% weight loss), cardiovascular risks.
- Diethylpropion (Amfepramon): An amphetamine-like anorectic, withdrawn from the European market in 2003 due to cardiovascular risk.
The Fen-Phen Disaster (1992-1997)
The combination of fenfluramine + phentermine (Fen-Phen) was the first anti-obesity treatment to achieve major commercial success in the United States. Prescribed to millions of patients, it was urgently withdrawn in 1997 after the discovery of:
- Cardiac valvulopathies in 30% of users
- Potentially fatal pulmonary arterial hypertension
- The withdrawal led to billions of dollars in compensation (American Home Products paid over 20 billion USD)
This scandal profoundly impacted the medical community and regulators, establishing lasting distrust towards pharmacological obesity treatments.
Orlistat: The Survivor (1998-Present)
Orlistat (Xenical, Alli) was approved in 1998 with a radically different mechanism: it blocks the absorption of dietary fats by inhibiting pancreatic lipases. Approximately 30% of dietary fats are excreted in the stool instead of being absorbed.
Efficacy: Modest weight loss of 3 to 5% on average. The response rate is low: only 30-40% of patients lose more than 5% of their weight.
Side effects: Steatorrhea (fatty stools), oily flatulence, fecal incontinence. These effects, though not dangerous, make the treatment difficult to tolerate and contribute to a high discontinuation rate of 50% at 1 year.
Orlistat remains available in France (by prescription for Xenical 120 mg, over-the-counter for Alli 60 mg) but is rarely prescribed since the arrival of GLP-1s.
Sibutramine: A Broken Promise (1997-2010)
Sibutramine (Sibutral/Meridia) was a serotonin and norepinephrine reuptake inhibitor. It reduced appetite and slightly increased energy expenditure.
Efficacy: Weight loss of 5 to 8%, superior to orlistat.
Withdrawal: The SCOUT study (2010) showed a 16% increase in cardiovascular events (heart attack, stroke) in at-risk patients. Sibutramine was withdrawn from the global market in 2010.
Rimonabant: The Cerebral Failure (2006-2008)
Rimonabant (Acomplia), developed by Sanofi, was a CB1 cannabinoid receptor antagonist. By blocking the endocannabinoid system, it reduced appetite and food pleasure.
Efficacy: Impressive, with 8 to 10% weight loss and an improvement in metabolic parameters.
Withdrawal: Rimonabant was withdrawn in 2008 (only 2 years after its launch) due to severe psychiatric side effects:
- Severe depression in 10% of users
- Suicidal ideation in 3%
- Several reported suicides
By blocking the endocannabinoid system in the brain, rimonabant not only suppressed food pleasure but also pleasure in general, causing severe anhedonia.
Mediator: The French Scandal (1976-2009)
Benfluorex (Mediator), although marketed as an antidiabetic, was widely prescribed off-label as an appetite suppressant in France. Chemically related to fenfluramines, it caused:
- An estimated 500 to 2000 deaths from valvulopathies and pulmonary hypertension
- A major health scandal that shook the French pharmacovigilance system
- Servier’s condemnation to billions of euros in damages
- A complete reform of the ANSM (formerly AFSSAPS)
Mediator was withdrawn in France in 2009, 10 years after the withdrawal of fenfluramines in the United States.
The Current Generation: Liraglutide 3 mg (2015)
The approval of liraglutide 3 mg (Saxenda) in 2015 marked the beginning of the GLP-1 era in obesity treatment:
- Efficacy: Weight loss of 5 to 8%, significantly superior to orlistat
- Safety: No cardiovascular toxicity (positive LEADER study)
- Physiological mechanism: Amplification of a natural satiety signal
- Drawback: Daily injection, moderate efficacy compared to later molecules
Comparative Table of Historical Treatments vs. GLP-1s
| Treatment | Weight Loss | CV Safety | Status |
|---|---|---|---|
| Amphetamines | Variable | Dangerous | Withdrawn |
| Fen-Phen | 10-15 % | Valvulopathies | Withdrawn (1997) |
| Sibutramine | 5-8 % | +16 % MACE | Withdrawn (2010) |
| Rimonabant | 8-10 % | Neutral | Withdrawn (2008) |
| Orlistat | 3-5 % | Neutral | Available |
| Mediator | Variable | Fatal | Withdrawn (2009) |
| Semaglutide 2.4 mg | 15-17 % | -20 % MACE | Available |
| Tirzepatide 15 mg | 20-22.5 % | Under evaluation | Available |
Key Takeaways
The history of anti-obesity treatments is marked by health catastrophes that explain the persistent distrust of obesity pharmacotherapy. GLP-1 agonists represent a fundamental breakthrough: for the first time, treatments produce significant weight loss (15-22%) with a favorable cardiovascular safety profile. Tirzepatide (Mounjaro), with its record weight loss of 22.5%, illustrates the progress made since the amphetamines of the 1950s.
FAQ
Are GLP-1s safer than older treatments?
Yes, significantly. Unlike amphetamines, Fen-Phen, or rimonabant, GLP-1 agonists have not shown cardiovascular or psychiatric toxicity. Semaglutide even demonstrated a cardiovascular benefit in the SELECT study.
Are Mediator and Mounjaro related?
No. Mediator (benfluorex) was a disguised fenfluramine, a molecule with known cardiovascular risk. Tirzepatide acts through a completely different mechanism (incretin receptors), with no chemical or pharmacological link to fenfluramines.
Is orlistat still useful?
Orlistat remains available, but its efficacy is much lower than GLP-1s (3-5% vs 15-22%). It may be considered for patients who refuse injections and cannot access oral GLP-1s.
Why do anti-obesity treatments have such a bad reputation?
Successive scandals (Fen-Phen, rimonabant, Mediator) established justified distrust. GLP-1s stand out due to the rigor of clinical studies (tens of thousands of patients, cardiovascular follow-up) that preceded their approval.
Could GLP-1s be withdrawn one day?
Zero risk does not exist, but current data are extremely reassuring. GLP-1 agonists have been used since 2005 (exenatide) with over 20 years of clinical experience, dozens of cardiovascular studies, and millions of patients treated.
Sources
- Colman E. Anorectics on trial: a half century of FDA régulation of prescription appetite suppressants. Ann Intern Med. 2005;143(5):380-385.
- Connolly HM et al. Valvular heart disease associated with fenfluramine-phentermine. NEJM. 1997;337:581-588.
- James WPT et al. SCOUT: sibutramine cardiovascular outcomes. NEJM. 2010;363:905-917.
- Christensen R et al. Rimonabant efficacy and safety. Lancet. 2007;370:1706-1713.
- IGAS. Rapport sur le Mediator (benfluorex). 2011.
- Lincoff AM et al. SELECT. NEJM. 2023;389:2221-2232.