Worldwide obesity tripled in just the last half century, and more people live in countries where there are greater overweight-related deaths than underweight-related deaths, WHO reports [1]. 

Obesity is an excess of body fat. As body fat increases, adipose tissues reach their capacity to store fat. This results in more fat circulating in the blood and improper accumulation in multiple tissues, including the liver and muscle [2]. When fat deposits in regions of the body it shouldn’t be, it causes inflammation, increases stress on the body cells, and accelerates the development of insulin-resistant tissue. 

Obesity is associated with various health conditions such as diabetes, cardiovascular diseases, strokes, and certain types of cancer [2]. In 2017 alone, around 4.7 million deaths worldwide were attributed to obesity [3]. This has placed an enormous burden on our healthcare system. In the US, obesity costs the healthcare system over $172 billion annually [4].  

In 2008, around 25.5 percent of adults were obese in the US, but by 2020, about 42.4 percent were obese [5,6]. The prevalence of obesity is rapidly growing, representing a major health threat for our society, which is why the medical world has been scrambling to find a solution for obesity [7].  

Weight-loss diets are the most popular solution to reducing body weight, but scientists have found that lost weight is often regained within a few months for several reasons. Some diets are generally too restrictive and difficult to follow long-term. Also, severely restricting caloric intake can decrease metabolism, making it difficult to maintain weight loss in the long run [7]. As a result, researchers have turned to pharmacotherapies to address this life-threatening epidemic. 

The first anti-obesity pills were created in the early 1900s. Given the complex nature of the body’s energy regulatory processes, the mechanism underlying these pills varied. Since hormones control our appetite and metabolism, researchers focused on ways to override these hormones as well as the way our body processes fat. Specifically, some of these pills worked by modulating hunger and satiety, limiting intestinal transportation of nutrients, or by directly changing energy expenditure [2]. 

Thyroid hormone supplements were one of the first anti-obesity pills to be introduced to the public. Thyroid hormones produced by the thyroid gland are long known to increase metabolic rates. Not only do thyroid hormones increase energy expenditure, but they also improve fat metabolism in the liver. 

However, excess activity of thyroid hormones can result in muscle and bone breakdown, as well as irregular heartbeats (cardiac arrhythmia) and heart failure [2]. This presents challenges in using thyroid hormones for weight management. Nevertheless, thyroid extracts have been shown to reduce body weight, and in the late 1900s, physicians would occasionally prescribe medications that strengthened the muscle contractions of the heart to reduce the cardiovascular effects of thyroid hormones [8]. 

In 1993, 2,4-Dinitrophenol (DNP),  a substance often used in manufacturing explosives, also found in dyes and herbicides, was identified to have weight lowering properties. DNP administration at doses of 3-5mg/kg per day was found to result in a loss of about 1.5kg of body weight per week [2]. These weight-lowering properties are due to DNP’s ability to increase metabolic rate by enhancing mitochondrial uncoupling, where heat production is favored over ATP synthesis [2]. 

Despite the impressive weight loss benefits of DNP, its potential is limited by adverse effects including hyperthermia, hyperventilation, high heart rate, extreme sweating,  nausea and vomiting [2]. Moreover, while a dose of 300mg per day was found to be tolerable and increased metabolic rate by 50%, later studies confirmed that acute administration of 20-50mg/kg of DNP can be lethal [2]. These adverse effects prompted the FDA to suspend DNP. 

Medications that have been approved by the FDA, however, include various types of amphetamines. Amphetamines gained popularity for their ability to suppress appetite [2]. In particular, methamphetamine desoxyephedrine  regulates appetite by stimulating the synthesis and release of a class of neurotransmitters like dopamine, catecholamines, in the central nervous system. 

This increases metabolic rates by upregulating the uptake of glucose in the peripheral tissue for ATP production. It also stimulates the hypothalamic neurocircuits that regulate hunger and satiety [2,9], meaning it can modulate food intake.  

Within the arcuate nucleus of the hypothalamus, there are two populations of neurons, neuropeptide Y (NPY) and agouti-related peptide (AgRP)-expressing AgRP/NPY neurons and pro-opiomelanocortin (POMC)-expressing POMC neurons, which work antagonistically to each other. POMC neurons project onto second-order neurons such as the paraventricular nucleus (PVN) and the lateral hypothalamus (LH) and send inhibitory signals for food intake [9]. 

On the other hand, fasting stimulates the AgRP/NPY neurons, which increase food uptake by also projecting on PVN and LH. That is to say, amphetamines work by inhibiting food intake through the stimulation of POMC neurons and inhibiting the activity of the NPY neurons [2]. Unlike other weight-loss drugs, three daily doses of 2mg desoxyephedrine can decrease body weight by as much as 24.5kg without any adverse effects [2]. 

However, amphetamines hold a risk for addiction since they act through the central reward system in the brain [2]. As a result, researchers were inspired to develop chemical-analogs that retained the appetite-suppressing effect but with fewer safety concerns [2]. 

By the 1960s, several amphetamine congeners such as Phentermine, Phendimetrazine, and Benzphetamine were developed and approved by the FDA for use to treat obesity [2,7]. However, the addictive potential was not ruled out, hence, the FDA restricted the use of amphetamine congeners to short-term treatments (only a few weeks). 

Phenmetrazine is another amphetamine congener drug that was approved for the treatment of obesity. Similar to amphetamines, phenmetrazine has sympathomimetic properties, enabling it to inhibit food intake by stimulating the release of norepinephrine and dopamine from the central nervous system, which suppresses appetite. 

Unfortunately, adverse effects were associated with this drug as well including, “tachycardia, heart arrhythmias, hypertension, convulsions, restlessness, agitation, vomiting, and diarrhea” [2]. There was at least one reported case of phenmetrazine poisoning. Due to the euphoric effect of phenmetrazine, as a result of increased dopamine release, it was misused for recreational purposes. Eventually, the commercialization of phenmetrazine was discontinued, and it was withdrawn from the market [2]. 

Later in 1994, Jeffrey Friedman identified an appetite-regulating hormone, leptin, produced by the white adipose tissue of the body [2]. Leptin acts to reduce food intake and to increase energy expenditure by stimulating POMC neurons and silencing neurons that express NPY and AgRP. Soon after his discovery, leptin deficiency was shown to result in obesity in mice and leptin replacement was shown to reverse obesity and improve insulin sensitivity [2].

 Indeed, exogenous administration of leptin was found to correct obesity in individuals with low or absent levels of leptin. However, leptin replacement is largely ineffective in decreasing body weight under conditions of common obesity, which are lifestyle-induced and not based on a loss of function mutation [2]. Moreover, some individuals have enough endogenous leptin however are leptin resistant, meaning they do not respond to leptin signaling. Dietary fat and sugar are crucial in leading to leptin resistance [2]. 

Another class of drugs known as the glucagon-like peptide 1 (GLP-1) agonists, which mimic the function of the GLP-1 hormone, have been shown to lower body weight and improve glucose metabolism [2]. When exposed to food, the intestines release GLP-1 to act on the pancreas to enhance insulin production and inhibit glucagon release, with little risk of hypoglycemia. The risk of low blood sugar associated with GLP-1 agonists is only increased when taking another blood sugar lowering medication at the same time [10]. GLP-1 also reduces food intake and hunger and promotes fullness. Weight loss can vary depending on the GLP-1 drug used and the dose. On average, however, weight loss can be anywhere between 1.5-2.5kg [10].             

Anti-obesity pills are a patient-friendly non-surgical approach to replicate the positive metabolic outcomes of bariatric surgery. However, the historical performance of weight-controlling drugs has been notably challenged [2]. Many have been withdrawn due to adverse effects that outweighed the benefits of treatment; others lacked effectiveness. 

In fact, researchers have found that most  “single-hormone pharmacotherapies evaluated for the treatment of obesity show limited efficacy to lower body weight, typically less than 5% and rarely more than 10% relative to placebo-controlled comparison treatment”[2]. It seems intuitive to expect that the co-administration of single hormones might improve the outcomes [2,11]. Currently, researchers are testing many unimolecular multi-agonist drugs (usually a gut hormone coupled with GLP-1) to treat obesity. While preclinical and clinical trials show possibly reduced adverse side effects, outpatient trials are still needed to evaluate the sustainability and safety of the drugs [11]. However, researcher Annie Hasib wrote that using multi-agonist drugs “may offer a more patient-centric non-surgical breakthrough for the treatment of obesity-linked metabolic disorders.”  [11]. 

References 

1. Obesity and overweight. (n.d.). Retrieved December 1, 2021, from https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight
2. Müller, T. D., Clemmensen, C., Finan, B., DiMarchi, R. D., & Tschöp, M. H. (2018). Anti-Obesity Therapy: From Rainbow Pills to Polyagonists. Pharmacological Reviews, 70(4), 712–746. https://doi.org/10.1124/pr.117.014803
3. Dai, H., Alsalhe, T. A., Chalghaf, N., Riccò, M., Bragazzi, N. L., & Wu, J. (2020). The global burden of disease attributable to high body mass index in 195 countries and territories, 1990–2017: An analysis of the Global Burden of Disease Study. PLoS Medicine, 17(7), e1003198. https://doi.org/10.1371/journal.pmed.1003198
4. Ward, Z. J., Bleich, S. N., Long, M. W., & Gortmaker, S. L. (2021). Association of body mass index with health care expenditures in the United States by age and sex. PLOS ONE, 16(3), e0247307. https://doi.org/10.1371/journal.pone.0247307
5. Inc, G. (2016, February 12). U.S. Obesity Rate Climbs to Record High in 2015. Gallup.Com. https://news.gallup.com/poll/189182/obesity-rate-climbs-record-high-2015.aspx
6. The State of Obesity 2020: Better Policies for a Healthier America. (n.d.). Tfah. Retrieved November 28, 2021, from https://www.tfah.org/report-details/state-of-obesity-2020/
7. What Are Anti-Obesity Medications and How Do They Work?: Scott D. Isaacs, MD: Endocrinologist. (n.d.). Retrieved November 1, 2021, from https://www.atlantaendocrine.com/blog/what-are-anti-obesity-medications-and-how-do-they-work
8. Digoxin as a Treatment for Heart Failure. (n.d.). Retrieved November 3, 2021, from https://www.webmd.com/heart-disease/heart-failure/heart-failure-treating-digoxin
9. Timper, K., & Brüning, J. C. (2017). Hypothalamic circuits regulating appetite and energy homeostasis: Pathways to obesity. Disease Models & Mechanisms, 10(6), 679–689. https://doi.org/10.1242/dmm.026609
10. Do any diabetes drugs help you lose weight? (n.d.). Mayo Clinic. Retrieved November 30, 2021, from https://www.mayoclinic.org/diseases-conditions/type-2-diabetes/expert-answers/byetta/faq-20057955
11. Hasib, A. (2020). Multiagonist Unimolecular Peptides for Obesity and Type 2 Diabetes: Current Advances and Future Directions. Clinical Medicine Insights. Endocrinology and Diabetes, 13, 1179551420905844. https://doi.org/10.1177/1179551420905844