Shannon Peters UCD School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland



Obesity is a worldwide epidemic and one that affects a large group of the Irish population. Our nation currently claims the bronze medal for the most obese country in the European Union (EU)1. Currently, it is estimated that 6 in 10 adults and 1 in 4 children are either overweight or obese in Ireland. It has also been shown that 75% of adults over 50 are overweight or obese2. Obesity is a complex medical condition that is the result of genetic susceptibility and environmental factors such as the prevalence of energy rich foods, sedentary lifestyles, and a lack of physical activity. As such, treatment of obesity is equally complex and involves numerous approaches. First line therapy in obesity treatment involves lifestyle modifications, including a change in diet and an increase in exercise. However, often this method alone is ineffective. To battle the bulge, a pharmacological agent can be prescribed in adjunct to these lifestyle modifications. Several pharmacologic agents have been developed over the last century that target a variety of regulatory mechanisms, although significant side effect profiles and toxicities have prevented their widespread use. This article reviews the past and current pharmacotherapies trialled in the treatment of obesity, as well as outlines their harms and potential benefits.




Introduction: ONe BIG Problem 

Obesity is a growing problem worldwide - literally and figuratively. In 2014, the World Health Organization (WHO) estimated that 1.6 billion adults aged 20 or older are overweight and among them, 600 million are obese3. In Ireland alone, the prevalence of obesity amongst men increased from 8% in 1990 to 26 in 2011 while among women it increased from 13% to 21% over the same time period4. Overweight is defined as a body mass index (BMI) greater than 25, whereas obesity is a BMI greater than 30. Being overweight or obese are risk factors for developing several serious illnesses including type II diabetes mellitus, cardiovascular disease, asthma, sleep apnoea, gallbladder disease, osteoarthritis, and certain types of cancer5. Unsurprisingly, obesity imposes a significant economic burden on society; in 2009 it was estimated that the direct and indirect costs associated with overweight and obesity in Ireland totalled €1.13 billion6.


Why we eat

The mechanisms mediating obesity are currently being researched extensively to develop a successful pharmacological agent that is not only effective, but also safe and practical to use. The neurohormonal system has been proposed as the focus for targeted therapy. The neurohormonal pathway can be categorized into afferent signals, central processing and efferent signals. Afferent signals include the hormones leptin, insulin and ghrelin, and short-acting gastrointestinal signals including cholecystokinin, pancreatic polypeptide, peptide-Y-Y, oxyntomodulin, enterostatin and glucagon-like peptide 1 (GLP-1). The afferent signals are transmitted to the central processing unit in the hypothalamus, specifically the arcuate nucleus (ARC, which contains orexigenic, or hunger stimulating, neurons and anorexigenic, or hunger inhibiting, neurons). Agouti-related peptide (AgRP) and neuropeptide Y (NPY) neurons are first-order orexigenic neurons, activated by ghrelin.

Conversely, the anorexigenic neurons, namely pro-opiomelanocortin (POMC) and cocaine and amphetamine-related transcript (CART) neurons, are activated by leptin. The efferent signals then transmit the information from the hypothalamus to other locations in the central nervous system to initiate downstream effects and regulate eating behaviours. The orexigenic pathway is mediated by the orexigenic peptides, melanin-concentrating hormone (MCH) and orexins A and B, and results in increased hunger and decreased energy expenditure. The anorexigenic pathway is mediated by thyrotropin releasing hormone (TRH) and corticotrophic-releasing hormone (CRH) and acts to decrease hunger and food intake. It is the balance of the orexigenic and anorexigenic pathways that is responsible for energy homeostasis, and maintenance of BMI.

Notable Drug Failures:

Over the past several decades, many pharmacological therapies have been recommended with the aim of battling the obesity epidemic. Attempts to decrease energy intake, increase energy expenditure, alter lipid metabolism and mimic caloric restriction have been trialled. However, many drugs used previously have been discontinued due to their potential for misuse or severe adverse effects profile. Some of the most notable anti-obesity drug failures include;

1. Dinitrophenol

Dinitrophenol was introduced in the 1930s and was regarded as a highly effective weight loss drug due to its ability to increase basal metabolic rate. Dinitrophenol diminishes the proton gradient in the electron transport chain and uncouples oxidative phosphorylation7. As a result, instead of synthesizing ATP via the proton gradient and ATP synthase, energy is dissipated as heat7. Adverse effects associated with dinitrophenol include: hyperthermia, tachycardia, diaphoresis and tachypnoea and the drug has been reported to cause death in over 60 cases in the literature7. Although effective in reducing weight, the extensive side effect profile and risk of death warranted removal of dinitrophenol from the market in 1938, less than 10 years after it was introduced8.

2. Amphetamines:

Shortly after dinitrophenol, amphetamines were proposed as a potential cure to obesity. Amphetamines primarily act to increase the release of norepinephrine from central adrenergic nerve terminals and enhance the sympathetic nervous system. Catecholamines released by the sympathetic nervous system act to increase the release of glucose and fats from storage for energy utilisation9. Therefore, amphetamines increase weight loss and decrease appetite9. The main side effects of amphetamines include tachycardia, palpitations, hypertension, nervousness, insomnia and constipation9. Amphetamines went out of favour in the early 1970s due to their potential for abuse, and severe side effects including hypertension and myocardial toxicity8. Notable amphetamines that have been trialled include aminorex, phenylpropanolamine and fenfluramine/phentermine. The 1960s saw the introduction of aminorex, a metabolite of cocaine. Aminorex was discontinued as it was shown to cause pulmonary hypertension with 50% mortality in those affected10. The 1970s saw the introduction of phenylpropanolamine, an indirect sympathomimetic that acts to increase noradrenaline release from presynaptic vesicles in the lateral hypothalamus9. It was also discontinued due to its potential to cause intracranial bleeding11. The combination drug, fenfluramine/phentermine, was introduced in the 1990s as a promising weight loss agent. Fenfluramine inhibits the reuptake of serotonin, and phentermine increases the release of norepinephrine9. Fenfluramine/phenteramine was shown to cause pulmonary hypertension and valvular heart disease12,13. The use of this combination drug was discontinued in 1997, but continued to create a legal and financial disaster into the 21st century14.

3. Rimonabant:

A cannabinoid receptor 1 (CB1) antagonist, rimonabant, was approved by the European Medicines Agency (EMA) in 2006 as a weight loss agent used to decrease appetite. Rimonabant blocks endogenous cannabinoids from binding to the CB1 receptor, which normally acts to increase appetite15. Side effects of rimonabant include depression and suicidal ideation, and for this reason the Federal Drug Administration (FDA) never approved rimonabant, and it was withdrawn in Europe in 200915.

"Success" Stories: 

The most prominent drug on the market today for weight loss is orlistat, a synthetic derivative of an endogenous lipase inhibitor, lipstatin. Orlistat is an inhibitor of pancreatic and gastric lipases that are required for the hydrolysis of dietary fat into free fatty acids and monoacylglycerols, which are then absorbed in the intestine16. Thus, orlistat prevents the uptake of free fatty acids via their fatty acid transporters in the intestine and renders only 30% of digested fats systemically absorbed8. A meta-analysis of 29 studies found that patients taking orlistat had a 2.9% greater weight loss compared to a placebo group and patients showed a significantly greater reduction in waist circumference and BMI17. Orlistat was approved by the FDA in 1999, and has since been made available over-the-counter in the USA and Europe. The main side effects of orlistat are gastrointestinal and include faecal incontinence, flatus, oily faecal spotting, urgency and soft stools. Patients taking orlistat may have decreased absorption of fat-soluble vitamins (vitamins A, D, E and K), and decreased absorption of certain drugs such as warfarin, amiodarone and cyclosporine17.

In 2012, after a static thirteen years in the anti-obesity medication realm, the FDA approved lorcaserin, a 5-HT2C agonist. Activation of 5-HT2C receptors increases anorexigenic signalling and decreases orexigenic signalling in the presynaptic area of ARC18. Lorcaserin is 15- to 100-fold more selective for 5-HT2C receptors than 5-HT2A or 5-HT2B receptors9. Previous agents with affinity for the 5-HT2A and 5-HT2B receptors demonstrated side effects including hallucinations and cardiovascular effects such as valvulopathy and pulmonary hypertension9. Adverse effects of lorcaserin include headache, upper respiratory tract infections, nausea, fatigue, diarrhoea, urinary tract infections, constipation and dry mouth9. Due to its nature as a serotonin agonist, there is also the risk of serotonin syndrome with lorcaserin use9. Lorcaserin is not licensed for use in Europe due to concerns over carcinogenicity, as well as psychiatric disorders and valvulopathy9

The FDA also approved phentermine/ topiramate extended release formulation in 2012. Phentermine, acts to increase norepinephrine, whereas topiramate has a much more complex mechanism of action9. Topiramate, which is used in the treatment of seizure disorders and migraine prophylaxis, induces satiety via GABA-mediated inhibitory activity, modulation of voltage gated calcium and sodium channels, inhibition of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate/kainite glutamate receptors, and inhibition of carbonic anhydrase19,20. In clinical trials, the combination drug has shown to decrease binge-eating behaviours and has decreased the number of episodes of binge eating, food cravings and addictive behaviour as well as weight21. The beneficial effects of this combination are thought to be due to its dual action on both the psychological aspect and neuroendocrine mechanism responsible for inducing weight loss. Adverse effects observed with phentermine/topiramate include paraesthesias, dry mouth, constipation, dysgeusia and insomnia22,23. The EMA has rejected the marketing application for phentermine/topiramate over worries of cardiovascular, psychiatric and cognitive effects associated with long-term use, teratogenicity and potential misuse by patients whom it is not intended8

Two years later, in 2014, another combination drug, buproprion/naltrexone, was added to the list of FDA approved anti-obesity medications. Buproprion, a drug also used for depression and smoking cessation, increases noradrenergic and dopaminergic neurotransmission via reuptake inhibition8. Buproprion has also been shown to stimulate POMC neurons, which release α-MSH and β-endorphin8. α-MSH binds to MC3 and MC4 receptors to inhibit food intake and induce satiety8. Inhibitory feedback on POMC neurons is mediated by β-endorphin binding to μ-opioid receptors, an effect that can be inhibited by naltrexone, an opioid antagonist24. Thus, both buproprion and naltrexone work together to prolong and potentiate the effect of anorexigenic POMC neurons. In phase III clinical trials, patients experienced an improvement in weight-related cardiac and metabolic parameters including waist circumference, HDL and triglycerides25. Patients also reported that their quality of life and control of eating were improved25. Adverse events observed with buproprion/naltrexone include nausea, constipation, headache, vomiting, dizziness, insomnia, dry mouth and diarrhoea25. The FDA has approved the drug but further post-marketing studies were requested to evaluate cardiovascular risk, dosing in renal and hepatic impairment and drug interactions8

Liraglutide, a GLP-1 analogue, was also approved by the FDA and EMA for management of obesity in 2014 and 2015, respectively. Liraglutide binds to the same receptors as endogenous GLP- 1. Therefore, it increases endogenous insulin secretion and has been licensed for use in type II diabetes mellitus since 200926. In a randomised controlled trial, patients treated with liraglutide exhibited 8.1% body weight loss at 56-week follow-up, as compared to 2.7% body weight loss in the placebo group27. Adverse effects associated with liraglutide include nausea, hypoglycaemia, diarrhoea, constipation, vomiting, headache, decreased appetite, dyspepsia, abdominal pain and increased lipase activity26. More serious adverse effects associated with the drug include acute pancreatitis, chest pain and bronchitis26. Concerns over thyroid malignancy with the use of liraglutide have been raised, due to results in rodent studies26. Thus, the FDA has required post-marketing surveillance for medullary thyroid carcinomas, and instructed that liraglutide not be administered to anyone with a family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 226.


Developing anti-obesity agents presents a unique challenge, as central pathophysiological mechanisms and neuroendocrine hormone dysfunction are involved. As such, targeted monotherapy is often ineffective as counter-regulatory mechanisms come into play and negate the pharmacological effects. Furthermore, many of the pharmacological agents used act centrally, causing side effects such as depression, hallucinations and suicidal ideation. Moreover, many of the older and several of the newer agents are derivatives of amphetamines, rendering cardiovascular side effects a significant problem. 

Historically anti-obesity medications have shown significant side effect profiles and as such newer agents are highly scrutinized by the FDA and EMA before marketing. The FDA requires that the difference in mean weight loss between the drug and placebo group is at least 5% for at least 1 year and statistically significant, and that the proportion of subjects who lose at least 5% of baseline body weight in the active product group is at least 35% and approximately double the proportion in the placebo controlled group28. Not surprisingly, the drug is critically examined for its potential to cause neuropsychiatric symptoms, cardiovascular toxicity (including pulmonary hypertension and valvulopathy), and its abuse potential.


Significant amounts of research and development have been completed in the field of obesity pharmaceuticals to minimal avail. In the UK, nearly 24% men and 26% women were estimated to be obese in 201129. This prevalence of obesity has been predicted to increase by 2050 to 60% of adult men and 50% of adult women29. Evidently, the available pharmacological options do not act as sufficient adjuvants to surgery and lifestyle interventions in controlling the obesity epidemic. Further investigation is warranted into optimising the benefits of pharmacological agents while minimising the adverse effects for these agents to be effective and widely accepted. Otherwise we will continue to have a massive problem in our hospitals and communities – no pun intended.





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