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Caution: New Weight Loss Drugs Often End Badly

April 22, 2023 at 3:05:21 PM

From the 1930s through now, new weight loss drugs have been a little scary. "DNP" was a 'miracle' weight loss drug that later proved dangerous and in the 1990s, 'Fen-Phen' became one of the worst events in pharmaceutical history. Accordingly, we should view today's newest weight loss drugs with a certain measure of caution.

Caution: New Weight Loss Drugs  Often End Badly

As a weight loss physician, I have witnessed the rise and fall of various obesity treatment drugs over the years. It is crucial to sound a note of caution about the use of GLP-1 drugs for weight loss, as their effectiveness in the real world may not live up to the expectations set by clinical trials¹. Additionally, as these drugs are used by millions of people, it is likely that unknown risks will emerge, such as the so-called "Ozempic face". In this essay, I will discuss the history of obesity treatments, the hype surrounding GLP-1 drugs, my personal concerns about their efficacy and safety, and the need for a broader perspective on weight loss solutions.

Size of the Problem

The obesity epidemic on Earth has reached unprecedented levels, with millions of people suffering from this condition worldwide. According to the World Health Organization, obesity has nearly tripled since 1975, and in 2016, more than 1.9 billion adults were overweight, with over 650 million being obese1. This public health crisis has led to a desperate search for effective weight loss treatments, with numerous drugs being developed and marketed over the years.

1930s: The First Weight Loss Drugs

The history of anti-obesity drugs dates back to the 1930s when Cutter and Tainter at Stanford University discovered the weight loss effects of dinitrophenol (DNP)2 — a chemical used during World War 1 in the munitions industry that caused weight loss in workers accidentally exposed to it. Initially promising, DNP was later found to be a dangerous drug that can cause death by hyperthermia (body temperature can rise as high as 110 degrees Fahrenheit in people taking DNP) and also caused cataracts, leading to its discontinuation in the late 1930s. Incidentally, the risks of DNP prompted one of the largest upgrades to the FDA in history. Amphetamines were used and abused for weight loss in the following decades, until the advent of non-amphetamine drugs like phentermine in the 1950s. These drugs were effective but sometimes had unpleasant side effects, limiting their long-term use to patients able to tolerate them.


The early 1990s saw the introduction of fen-phen, a combination of fenfluramine and phentermine, which was hailed as a "game-changer" for obesity treatment3. However, in 1997, fen-phen was withdrawn from the market due to serious heart valve damage. The subsequent introduction of Meridia, Qsymia, Contrave, and Lorcaserin followed a similar pattern, with initial promise giving way to safety concerns or underwhelming results.

GLP-1 agonists, derived from a prey-paralyzing poison in the saliva of the Gila monster, were initially used to treat type-2 diabetes6. Over time, they have been adopted for obesity treatment at higher doses, with clinical trial data showing significant weight loss. Social media influencers and celebrities have heavily promoted these drugs, and even Weight Watchers recently announced its intention to partner with physicians to offer GLP-1 drugs to customers. The hype surrounding these drugs is currently at an all-time high.

Despite the enthusiasm, I have concerns about the use of GLP-1 drugs for weight loss. In my experience prescribing them, they can produce substantial weight loss but not to the extent that they are “game changers”. Older drugs like phentermine often work almost as well. Moreover, GLP-1 drugs can cause side effects such as nausea, vomiting, severe gastroesophageal reflux, and diarrhea, leading many patients to discontinue their use.


The weight loss achieved with these drugs can be "brittle," with rapid regain occurring upon drug cessation. The high cost of GLP-1 drugs, such as Wegovy, which can reach up to $900 per month after manufacturer discounts, coupled with limited insurance coverage and the potential for rapid regain, raises concerns about their long-term viability as a weight loss solution. The increasing number of social media discussions about rapid weight regain with these drugs warrants further investigation.

It is essential to consider the possibility that GLP-1 induced weight loss may not be sustainable. The human body has multiple redundant systems to protect body weight, and when one system is defeated, others often compensate, leading to weight regain. This phenomenon has been observed in bariatric surgery patients, who, on average, regain almost half of their lost weight within five years following the procedure.

Lastly, it is crucial to consider the potential unknown risks associated with the widespread use of GLP-1 drugs. As with many new medications, unforeseen side effects may emerge as millions of people use them. While I am not suggesting that there are definite risks, it is essential to remain vigilant. One such concern is the facial lipodystrophy, or "Ozempic face," associated with semaglutide use. There is growing evidence that this side effect is real and not insignificant.

In conclusion, the history of weight loss drugs has repeatedly shown that initial excitement often fades as the real-world efficacy and safety of these treatments are evaluated. GLP-1 drugs may not be the game-changers that many hope for, but that does not mean they are without value. As healthcare providers, we must approach new treatments with cautious optimism, carefully weighing the potential benefits and risks, and ensuring that our patients receive the most appropriate care for their individual needs. The pursuit of effective weight loss treatments will continue, and while GLP-1 drugs may play a role, it is vital to maintain a broader perspective on the complex issue of obesity and its management.


  1. World Health Organization. (2021). Obesity and overweight.

  2. Tainter, M. L., Cutting, W. C., & Stockton, A. B. (1934). Use of dinitrophenol in nutritional disorders: a critical survey of clinical results. The American Journal of the Medical Sciences, 188(6), 784-793.

  3. 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. New England Journal of Medicine, 337(9), 581-588.

  4. Eng, J., Kleinman, W. A., Singh, L., Singh, G., & Raufman, J. P. (1992). Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. The Journal of Biological Chemistry, 267(11), 7402-7405.

  5. Karmali, S., Brar, B., Shi, X., Sharma, A. M., de Gara, C., & Birch, D. W. (2013). Weight recidivism post-bariatric surgery: a systematic review. Obesity Surgery, 23(11), 1922-1933.

  6. van Can, J., Sloth, B., Jensen, C. B., Flint, A., Blaak, E. E., & Saris, W. H. M. (2014). Effects of the once-daily GLP-1 analog liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism in obese, non-diabetic adults. International Journal of Obesity, 38(6), 784-793.


Additional Reading

  • Wadden, T. A., Hollander, P., Klein, S., Niswender, K., Woo, V., Hale, P. M., & Aronne, L. (2013). Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE Maintenance randomized study. International Journal of Obesity, 37(11), 1443-1451.


  • Pi-Sunyer, X., Astrup, A., Fujioka, K., Greenway, F., Halpern, A., Krempf, M., ... & Wilding, J. P. (2015). A randomized, controlled trial of 3.0 mg of liraglutide in weight management. New England Journal of Medicine, 373(1), 11-22.


  • Marso, S. P., Daniels, G. H., Brown-Frandsen, K., Kristensen, P., Mann, J. F., Nauck, M. A., ... & Buse, J. B. (2016). Liraglutide and cardiovascular outcomes in type 2 diabetes. New England Journal of Medicine, 375(4), 311-322.


  • le Roux, C. W., Astrup, A., Fujioka, K., Greenway, F., Lau, D. C. W., Van Gaal, L., ... & Wilding, J. P. H. (2017). 3 Years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial. The Lancet, 389(10077), 1399-1409.


  • Davies, M. J., Bergenstal, R., Bode, B., Kushner, R. F., Lewin, A., Skjøth, T. V., ... & Wilding, J. P. H. (2018). Efficacy of liraglutide for weight loss among patients with type 2 diabetes: the SCALE diabetes randomized clinical trial. JAMA, 314(7), 687-699.


  • O'Neil, P. M., Birkenfeld, A. L., McGowan, B., Mosenzon, O., Pedersen, S. D., Wharton, S., ... & Wilding, J. P. H. (2018). Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial. The Lancet, 392(10148), 637-649.


  • Wilding, J. P. H., Batterham, R. L., Calanna, S., Davies, M., Van Gaal, L. F., Lingvay, I., ... & Pi-Sunyer, X. (2021). Once-weekly semaglutide in adults with overweight or obesity. New England Journal of Medicine, 384(11), 989-1002.


  • Apovian, C. M., Aronne, L. J., Bessesen, D. H., McDonnell, M. E., Murad, M. H., Pagotto, U., ... & Still, C. D. (2015). Pharmacological management of obesity: an endocrine Society clinical practice guideline. The Journal of Clinical Endocrinology & Metabolism, 100(2), 342-362.


  • Khera, R., Murad, M. H., Chandar, A. K., Dulai, P. S., Wang, Z., Prokop, L. J., ... & Singh, S. (2016). Association of pharmacological treatments for obesity with weight loss and adverse events: a systematic review and meta-analysis. JAMA, 315(22), 2424-2434.


  • Kushner, R. F., & Sorensen, K. W. (2020). Lifestyle medicine: the future of chronic disease management. Current Opinion in Endocrinology, Diabetes, and Obesity, 27(5), 301-307.


  • Ryan, D. H., Kahan, S., & Fujioka, K. (2020). New and emerging pharmacologic treatments for obesity. Endocrine Reviews, 41(6), 795-824.


  • Bays, H. E., & Fujioka, K. (2021). Current and future prescription pharmacologic agents for the treatment of overweight and obesity. Endocrine Practice, 27(1), 69-81.


  • Mullard, A. (2021). 2020 FDA drug approvals.


  • Nature Reviews Drug Discovery, 20(2), 85-90.


  • Kushner, R. F., & Sorensen, K. W. (2020). Lifestyle medicine: the future of chronic disease management. Current Opinion in Endocrinology, Diabetes, and Obesity, 27(5), 301-307.


  • Astrup, A., & Rossner, S. (2000). Lessons from obesity management programmes: greater initial weight loss improves long-term maintenance. Obesity Reviews, 1(1), 17-19.


  • Swinburn, B. A., Kraak, V. I., Allender, S., Atkins, V. J., Baker, P. I., Bogard, J. R., ... & Devarajan, R. (2019). The global syndemic of obesity, undernutrition, and climate change: the Lancet Commission report. The Lancet, 393(10173), 791-846.


  • GBD 2015 Obesity Collaborators. (2017). Health effects of overweight and obesity in 195 countries over 25 years. New England Journal of Medicine, 377(1), 13-27.

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