Flavour of the Week / Practical Practice

Pharmaceutical Treatment of Obesity: The 20th Century


Look out Orlistat, there’s a new kid in town! Several weeks ago the FDA in the US approved the use of a new weight loss medication, Belviq – the first such medication to be approved in 13 years. To be “used in combination with a reduced-calorie diet and exercise to combat obesity”, Belviq, or lorcaserin, works by activating serotonin receptors, stimulating satiety and satisfaction; clinical trials have shown a modest 5% weight loss with the drug in combination with diet and exercise (1,2).

Pharmacologic attempts to control obesity have a long and storied history, not all good (3). In honour of newbie Belviq (though still not approved in Canada), we’re taking a look at the good and bad that have come before this newest weight loss drug.

This installment will cover up to the end of the 20th century. We call this one from laxatives to Fen-Phen. Stay tuned for next week’s breakdown of highlights and lowlights of the last 12 years.

As early as the 2nd century AD, physicians have used the laxative and vomiting-inducing effects of some herbs for the purposes of weight loss. While these methods are still, unfortunately, popular today, things have changed a lot since in terms of what physicians recommend for obesity management. It’s been a bumpy road though!

1920s: “Modern day” pharmaceutical treatment of obesity begins with the simple observation that people with hypothyroidism treated with thyroid hormone lose weight – good for everyone, right? Thyroid hormone is given as the first weight loss drug (4), though the induction of classic hyperthyroidism takes the shine off this new use pretty quickly!

1933: 2,4-dinitrophenol (DNP) is introduced as a weight loss drug. Shown to dramatically increase metabolic rate and cause rapid weight loss, DNP alters mitochondrial proton transport and uncouples oxidative phosphorylation. Essentially, DNP interferes with your body’s ability to convert fuel to energy (as ATP); instead heat is produced, and you rapidly draw on fat stores to keep up with energy demands, particularly as DNP dose increases (5).

In addition to increased metabolic rate, DNP also has some nasty side effects related to the production of excess heat including hyperthermia, tachycardia, diaphoresis (excessive sweating), and even death. (5). Discontinued as a weight loss drug in physician practices in 1938, DNP is still available over the internet and remains popular with bodybuilders and athletes cutting weight. Still causing poisoning and deaths too!

1935: The stimulant and weight loss effects of amphetamines are first recognized (6). Suppressing appetite and increasing alertness, amphetamines were extremely popular as prescription and off-label weight loss treatment for DECADES.

1959: Phentermine, a stimulant with similar chemical properties to amphetamines, is approved as an appetite suppressant (7). Much later, phentermine would provide the “phen” in Fen-Phen. Current clinical trials are looking at a combination of phentermine and topiramate, an anticonvulsant, in obesity management (8).

1963: Given rampant prescription and off-label use of weight loss medications (and the coinciding link between thalidomide and birth defects), the FDA cracks down and amends the Food, Drug and Cosmetics Act. For the first time (yikes!), medications must first show efficacy and safety before they can be marketed.

1967: It wasn’t until eight women died in Oregon (and more followed in other states) due to the so-called “rainbow pill” combination of amphetamines, thyroid hormones, diuretics, barbituates and laxatives that the government intervened (9). Senate investigations halted the practice of these multiple-pill regimens, though individual amphetamine use was still common.

1973: Putting the future “fen” in Fen-Phen, fenfluramine, a serotonin-release stimulating drug, is approved (10). This non-amphetamine medication was touted to have fewer side effects, though that turned out to not be the case…

1979: Amphetamines are banned as prescription weight loss drugs and restricted amphetamine use to other conditions.

1992: Fen-Phen, a prescription combo of fenfluramine and phentermine, is born after researchers demonstrate initial 10% weight loss in an RCT study (11), though results didn’t last once medication was stopped (12). Despite this, Fen-Phen became extremely popular and frequently used.

1996: Dexfenfluramine (brand name Redux), with a similar serotonin-increasing effect to fenfluramine, is approved as a weight loss medication (13).

1997Fen-Phen and Redux are removed from the market after building concerns related to increasing cardiovascular disease risk with both medications.

No Baloney’s advice. To know where we are going, we need to look at where we’ve been. The magic bullet still hasn’t been found, despite what Dr. Oz may plug and the same caveat always applies – “to be used with diet and exercise”!

Join us next week as we look at contemporary weight loss medications, chronicling discoveries and letdowns in the 21st century.

References:

  1. O’Neil PM, et al. Randomized placebo-controlled clinical trial of lorcaserin for weight loss in type 2 diabetes mellitus: the BLOOM-DM study. Obesity (Silver Spring) 2012; 20:1426-36.
  2. Fidler MC, et al. A one-year randomized trial of lorcaserin for weight loss in obese and overweight adults: the BLOSSOM trial. J Clin Endocrinol Metab 2011; 96:3067-77.
  3. Derosa G, Maffioli P. Anti-obesity drugs: a review about their effects and their safety. Expert Opin Drug Saf 2012; 11:459-71.
  4. Kaptein EM, Beale E, Chan LS. Thyroid hormone therapy for obesity and nonthyroidal illnesses: a systematic review. J Clin Endocrinol Metab 2009; 94:3663-75.
  5. Grundlingh J, Dargan PI, El-Zanfaly M, Wood DM. 2,4-dinitrophenol (DNP): a weight loss agent with significant acute toxicity and risk of death. J Med Toxicol 2011; 7:205-12.
  6. Lesses MF, Myerson A. Human autonomic pharmacology. XVI. Benzedrine sulfate as an aid in the treatment of obesity, 1938. Obes Rev 1994; 2:286-92.
  7. Sehnert KW.  Development of phentermine, an appetite-control drug. Clin Med 1963; 70:400-3
  8. Garvey WT, et al. Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. Am J Clin Nutr 2012; 95:297-308.
  9. Fineberg SK, Snyder C, Henry R, Goddard JL. No end to the rainbow. Nutrition Today 1968; 3(2):24-5.
  10. Stunkard A, Rickels K, Hesbacher P. Fenfluramine in the treatment of obesity. Lancet 1973; 1:503-5.
  11. Weintraub M, et al.  Long-term weight control study. I (weeks 0 to 34). The enhancement of behavior modification, caloric restriction, and exercise by fenfluramine plus phentermine versus placebo. Clin Pharmacol Ther 1992; 51:586-94.
  12. Weintraub M, et al. Long-term weight control study. V (weeks 190 to 210). Follow-up of participants after cessation of medication. Clin Pharmacol Ther 1992; 51:615-8.
  13. Mathus-Vliegen EM, van de Voorde K, Kok AM, Res AM. Dexfenfluramine in the treatment of severe obesity: a placebo-controlled investigation of the effects on weight loss, cardiovascular risk factors, food intake and eating behaviour. J Intern Med 1992; 232:119-27.
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3 thoughts on “Pharmaceutical Treatment of Obesity: The 20th Century

  1. Pingback: TGIF | No Baloney

  2. Pingback: Pharmaceutical Treatment of Obesity: The 21st Century | No Baloney

  3. Pingback: TGIF | No Baloney

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