Why are anti-obesity drugs stigmatized?

Abstract

Obesity is a common and morbid disease, but its treatment remains far from ideal. Many doctors, regulatory agencies, media outlets and patients consider lifestyle modification as the only possible intervention. Pharmacological agents, although with limitations, are useful weapons but are highly stigmatized. Some reasons for this stigma are discussed in this editorial and include: the failure of short-term medication use to achieve long-term results (due to the chronic and recurrent condition of obesity); common perception of obesity as a lifestyle choice; difficulty to treat obesity in the primary care setting; less than desired weight-loss results with medications; misuse of medications for cosmetic reasons; and unfavorable history of other anti-obesity drugs that were withdrawn in previous decades.

Keywords:

• anti-obesity
• efficacy
• lorcaserin
• orlistat
• safety

1. Introduction

In this issue of “Expert Opinion on Drug Safety” we reviewed the efficacy and safety of two anti-obesity drugs, lorcaserin and orlistat [1]. They are the only FDA-approved monotherapy options for long-term use (phentermine, the most prescribed anti-obesity drug in the USA, is approved on label for short-term use only, as well as other catecholaminergic drugs; and phentermine/topiramate and bupropion/naltrexone are a single pill combination of two different drugs). Both drugs, however, are associated with modest weight loss of ∼ 3% over placebo, although a parcel of their users can achieve more substantial weight loss (assessed as 5 and 10% weight loss responders) and are those who will most likely benefit from its treatment [1].

Being a common disease, with increasing rates worldwide and associated with increased disability, morbidity and mortality, it is frustrating for obesity specialists that its treatment is far from ideal, with few available options [2-4]. Fortunately, in the last years, the FDA has apparently been moving towards a more comprehensive view of obesity as a disease, with the approval of newer drugs [5].

In this editorial, we would like to discuss issues related to the difficulty of accepting that obesity needs pharmacological treatment. This difficulty comes not only from regulatory agencies, but also from non-specialist doctors, patients and the media. We have summarized six commonly heard assumptions (at least in Brazil) and scrutinized them based on scientific evidence and personal opinion.

2. Does obesity require pharmacological treatment?

2.1 Obesity is a chronic and recurrent condition and short-term use of medications will lead to weight regain after discontinuation

The National Institutes of Health stated, in 1998, that “obesity is a chronic disease, and both the patient and the practitioner need to understand that successful treatment requires a life-long effort” [6]. Unfortunately, this is not always perceived by patients, the media and even many doctors. Many efforts are made to ‘lose weight’, with magical diets and pills and very little is said about ‘maintaining your weight after weight loss’ [7], leading apparently successful weight-loss programs in the short term to prove ineffective in the long term [8-10]. The use of medications for weight loss will probably work during its use, but without efforts to maintain the new weight, after its discontinuation, the lost weight will probably return [7,11]. So, any medication used to treat obesity must be safe for use in the long term, as its use should be, for at least the majority of obese patients, continuous [11]. This is a situation, which occurs with many known metabolic diseases, such as diabetes, hypertension and hypercholesterolemia, all for which the use of medications on a long-term basis is well accepted [12-14]. Long-term surveillance is necessary with any drug of chronic use and should be no different with obesity. Waiting, however, until long-term data are definitive is not economically feasible for its producers and will delay potentially useful options for many decades.

2.2 Obesity is not fully recognized as a disease and it is commonly defined as a lifestyle choice

In 1998 the NIH recognized obesity as a disease, and several other respected associations have done so since, the latest being the American Medical Association in 2014 [15]. The concept, however, is not accepted by all [16,17]. As many doctors, patients and sections of the media see obesity as an unhealthy choice, easily treated by lifestyle changes, it seems to be incongruent for them to use a pill to solve a problem you can solve by yourself [16,18-20]. The number of articles, which focus on lifestyle changes to tackle obesity, is overwhelmingly high, with similarly disappointing results [21,22] and they should be analyzed as strong evidence of limited results. Of course, there are a percentage of patients able to loose and maintain considerable amounts of weight in the long term without any medication, which varies from study to study. Everyone knows personally someone who has done it, but we are talking about evidence: case reports are not a rule, they are the exception [23]. Unfortunately, many members of regulatory agencies think in that way, which helps old drugs to be prohibited and new ones not to be approved [24].

2.3 Weight loss with known anti-obesity drugs is generally less than desired and not enough to ‘normalize’ BMI

It is common to read in articles that the median weight losses with anti-obesity drugs are small and the risks of side effects are higher than their possible benefits [16,24]. First, it is well known that in metabolically unhealthy obese individuals, a weight loss of 5 – 7% is sufficient to lead to an important improvement in cardiovascular risk factors, osteoarthrosis or sleep apnea, even if the achieved weight is far from a ‘normal’ Body mass index (BMI) of 25 kg/m² [25-27]. Second, the weight loss responses are very heterogeneous and in an intervention group there are individuals with no response and individuals with brilliant responses [28-33]. Obesity specialists know that and look more closely for data on the percentage of good responders, which can vary from drug to drug, permitting a better drug to be found for each patient. In clinical practice, patients who do not respond to the drug will discontinue it, leaving the continuous use to those that have more benefits. Third, weight-loss data from clinical trials are placebo subtracted [28-33]. Placebo groups generally receive some lifestyle counseling and there is also sometimes a lead-in period before the start of the study, so the results seen during the trial can be misleading, as there is already a period of weight loss before the trial [28]. Finally, the argument that it is not worth using anti-obesity drugs because of poor results is not sustainable as there are a vast number of patients (but clearly not all) that benefit greatly from their use [28-33].

2.4 Obesity is a common condition and is normally assessed in primary care

Unfortunately, this is true and obesity rates are growing in developed and developing countries [34]. The potential consumers of anti-obesity drugs are incalculable, so even a very rare side effect must be taken into consideration. Hypothetically, if a rare disease attacks 1% of population and the medication used to treat it provokes serious side effects in 10% of consumers, the public health burden will be the same than an anti-obesity drug with 0.33% of side effects, considering a population of 30% obese. This is a fear that all regulatory agencies have and this is quite a fair argument about rigorous surveillance. Of course, not all obese patients desire to use weight-loss pills and maybe not all of them need to. One main issue in obesity research is to better understand, which obese patient will benefit more from treatment. Recently, the terms metabolically healthy and unhealthy obese are being used more [35], but there is still quite a lot controversy as metabolically healthy obese appears to have higher disability and maybe mortality than the general population [36,37].

Another important point is that, as a common disease, the majority of patients should be ideally treated at primary care, as there are not enough specialists to treat all the obese patients. This is a critical point as obesity is a difficult disease to tackle and frequent visits to the doctor is one of the major predictors of successful weight loss [38]. Prescribing weight loss drugs without appropriate support, which is generally given by specialists, will result in less than expected results and a higher risk of side effects from a drug. An ‘obesity stigma’ and ‘obesity bias’ are another common finding in primary care [18,39].

2.5 Weight loss is a common desire in clinical practice, even for non-obese patients

Of course, weight is also an aesthetic question and it is very common that patients wish to lose weight [39,40]. Many of them are not obese, or even overweight, by BMI criteria [40,41]. Easy access to weight-loss drugs will lead to their use by people who do not need them, increasing the potential side effects profile and balancing the risk-benefit ratio to the wrong side. Weight-loss drug abuse exists and should be controlled [42]. This is a particular problem in Brazil [41,43,44], but with rigorous regulatory agencies to tackle the black market and encourage responsible prescription by doctors, this should not be a reason to ban old drugs or not allow newer drugs to enter the market and thus harming obese patients who would benefit from their availability.

2.6 Many anti-obesity drugs were banned due to unacceptable side effects, so newer drugs are probably also detrimental

Unfortunately, in the last decades many anti-obesity drugs were banned due to unacceptable side effects [5,45,46]. Thermogenic drugs that activate the sympathetic system, such as ephedrine and other drugs still used in ‘magic pills,’ are generally associated with an increased risk of cardiovascular disease [47,48] Fenfluramine was withdrawn from the market due to its valvulopathy risk [49]. Rimonabant was withdrawn from the countries it was approved (it was not an FDA-approved medication) due to psychiatric side effects, including suicide [50]. Sibutramine was removed from most markets after the SCOUT study demonstrated a 16% increase in non-fatal cardiovascular events in a high-risk population [29]. All of these examples should prompt us to look carefully at the safety profile of anti-obesity drugs, but in our opinion, at least with sibutramine, the withdrawal was done without careful analysis and many flawed arguments used in the last paragraphs were mistakenly used, as a recent subanalysis revealed a reduction in cardiovascular events in patients who lost weight in the trial, either in the placebo or sibutramine group [51]. As the prohibited drugs have very different mechanisms of action, we cannot generalize and think that any potential anti-obesity drug is unacceptably harmful.

3. Conclusion

In conclusion, although we should always be concerned about drugs that are used on a chronic basis by a significant proportion of the population, and with a risk when used by people who do not benefit from them, we should not let our fears overcome our hopes of improving treatment options for a hazardous and epidemic condition, with complex physiopathology.

Declaration of interest

A Halpern participated in advisory boards for Novo Nordisk for their product liraglutide. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.