Opinion piece: Why medicinal interventions for obesity are not a bad thing

The prevalence of obesity has been steadily increasing over recent decades, and so far public health interventions including dietary and lifestyle guidelines have fallen short on the impact needed to curtail such an epidemic. Unlike in other disease areas, there seems to be an unwillingness to accept medicinal interventions for weight loss, especially in the nutrition space. In this article, I'll hopefully address some of these concerns and share my thoughts on the topic.

Before we get started, it's first important to define what we mean by medicinal interventions, which aren't your stereotypical 'fat burner' supplement sold at your local health store. These are evidence-based pharmacological therapies that have been tested across clinical trial phases exhibiting an acceptable safety and efficacy profile. In the context of obesity treatment, these are labelled 'anti-obesity medications', with the aim to help patients who struggle with obesity to lose weight. While these therapies are few and far between, over recent years, the evolution of pharmacotherapy for obesity has opened the door to some promising new therapies.

What is the goal in obesity pharmacotherapy? 

From a pharmacodynamic perspective, the underlying goal in obesity treatment is to develop a therapy that induces weight loss. For that to happen, it's imperative to understand the causes of obesity and what drives humans to eat beyond our metabolic needs. It has been proposed that maladaptive hedonic and hunger signals in an obesogenic environment is one factor in its initiation and maintenance. [1]

Rosenbaum and colleagues, amongst others [2,3], put forward the concept of humans evolving to preserve adiposity and the surplus of energy storage, in what has been for most of our evolution a food-restricted environment. In recent years, our understanding of what regulates appetite and energy balance has vastly improved, with the neuroendocrine system thought to centrally regulate energy homeostasis [4]. However, if the homeostatic nuclei involved in energy balance is wired in accordance with a food-restricted environment, then the speedy transition from food scarcity to an overabundance builds the necessary framework for obesity to develop.

Identifying the hedonic and satiety nuclei in the brain responsible for regulating food intake is, therefore, a major pharmaceutical target. Glucagon-like-peptide 1 (GLP-1) is one signal that is generated in response to food acting on numerous regions throughout the central nervous system. It is involved in the satiety response following a meal, signalling distinct nuclei in the brainstem and hypothalamus to elicit feelings of fullness. Interestingly, emerging literature proposes roles beyond satiety, as it is thought that GLP-1 is also heavily involved in the reward response and motivation towards food. The role of GLP-1 in maladaptive reward responses has led to research exploring its utility in other reward behaviours, such as alcohol and drug addiction [5].

It is no surprise then that GLP-1 is a pharmaceutical target for the treatment of obesity, and numerous clinical trials have already highlighted the potential of GLP-1 targets to reduce energy intake and induce weight loss [6,7].

Away from the old and onto the new

Anti-obesity medications have been licensed now for many years, since 1959 when the FDA approved phentermine, a trace amine-associated receptor 1 (TAAR1) agonist [8]. Since then, an array of different classes of anti-obesity drugs have been developed and many are still prescribed today. The mechanisms that regulate energy balance have a considerable overlap with other physiological functions which makes targeting these mechanisms without producing undesirable side effects extremely difficult. There are many anti-obesity drugs that do not have the best safety profiles which have led to some being withdrawn from the market, and others being used sparingly [8].

Recent progress in our understanding of the neuroendocrine system and how it regulates appetite, food intake and energy expenditure has driven the construction of more targeted and less toxic anti-obesity drugs, through specifically targeting peptides involved in the regulation of appetite, like GLP-1. In this article, we are focussing on pharmaceutical GLP-1 targets, rather than older anti-obesity drug classes, but with the objective to shed light on why there's nothing inherently wrong with using drugs to help treat obesity.

  • A depiction of the synergy between the brain and GI tract in regulating energy balance. GLP-1 and other appetite-regulating peptides target distinct regions in the hypothalamus and brainstem that govern energy intake. Click here to learn more about the brain's role in appetite regulation.

Before the emergence of Semaglutide (which we will discuss in detail later), GLP-1 receptor agonists, which increase the secretion of GLP-1 within the body, were originally approved by the FDA only for the treatment of diabetes, as GLP-1 is an incretin hormone accounting for a large proportion of insulin secretion following a meal [9, 10]. It was the concomitant weight loss observed in the clinical trials in diabetics which highlighted the potential utility of these agents to treat obesity.

Compared to control subjects, the use of daily liraglutide, weekly or daily exenatide (both GLP-1 receptor agonists) in subjects with and without diabetes induced a significant amount of weight loss compared to control subjects [11].

An interesting case study by Zoicas and colleagues (2013) found GLP-1 receptor agonists to be effective in treating hypothalamic obesity, a condition characterized by a malfunctioning hypothalamus that causes excessive weight gain. Zoicas found the use of GLP--1 receptor agonist over an average duration of 24 months helped 8/9 hypothalamic obese subjects achieve an average weight loss of 13.1kg, ranging from 9kg to a massive 22kg loss over the study period [12].

The successful clinical trials with exenatide and liraglutide generated widespread interest in GLP-1 based therapies. Although, a big barrier in their adherence and maintenance for a large proportion of patients is the dosing regimen of once-daily injections (due to their short half-life). A method by which the half-life can be prolonged is through targeting binding sites on human serum albumin (HSA), a proven and versatile carrier for therapeutic proteins and peptides (through fatty acid linkers) with a substantially longer half-life due to its low rate of renal clearance. As HSA facilitates the transportation of fatty acids, finding the most effective fatty acid linker to bind to a GLP-1 agonist with high albumin affinity can allow for a more prolonged half-life. Eventually, this led to the development of Semaglutide, requiring just one dose a week [13].

The emergence of Semaglutide

Semaglutide is the subject of an ongoing clinical trial program designed to investigate the efficacy of Semaglutide on weight loss, in addition to other metabolic parameters. The STEP clinical trial program is a series of 1-8 clinical trials that are ongoing, with the publication of the STEP 1 clinical trial earlier this year highlighting the potential of this agent to make a real impact in obesity treatment [14]. Interestingly, Semaglutide has previously demonstrated a superior effect on weight loss in obese participants compared to Liraglutide [15].

The STEP 1 clinical trial is a randomized, double-blind study where 1961 overweight or obese participants were randomly assigned to receive 2.4mg of Semaglutide once a week for 68-weeks, or placebo, with both groups receiving lifestyle advice [16]. Not only is a long-term prospective randomised clinical trial important to assess the safety profile of the drug, it's also key to observe whether a sustained weight loss effect is present, as we know from dietary interventions weight loss is usually transient, followed by weight re-gain [17].

Over the 68-week period, participants in the Semaglutide group lost on average of14.9% of body weight (15.3kg) relative to 2.4% (2.6kg) in the placebo group. More than 85% of participants in the Semaglutide arm lost at least 5% of their body weight.

If we take a step back and observe the reduction in body weight in the Semaglutide group, could you imagine the frenzy in the nutrition world if these results were reproduced by a diet? An average of 15.3kg weight loss is of course clinically significant and far superior to results from other available anti-obesity medications. Not to mention, both groups did receive lifestyle support, including dietary advice, which may explain the small reduction in body weight observed in the control arm too.

After this study was published, I saw a hefty amount of scepticism in the nutrition space. Scepticism and critical thinking is of course important and warranted, but much of the scepticism wasn't directed towards the data itself, but the method of weight loss, drugs. Many seem uncomfortable with the idea of treating obesity with pharmaceutical agents, maybe because obesity management, unlike other areas, has for so long been isolated to lifestyle interventions adopting more holistic approaches. While dietary lifestyle interventions are certainly helpful and will always be an integral part of obesity management, it would be outrageous to neglect effective medicinal therapies on the basis of them being drugs.

Understanding the risks - are they worth it? 

Aside from the fact that these are drugs, there is of course concerns surrounding the safety profile of Semaglutide. It's important to understand that each anti-obesity drug class will have different safety profiles, grouping them together is extremely misleading. It's also important to keep in mind that there's an extremely strict pharmacovigilance process that conducts the fine balancing act of whether the drug benefits are determined to outweigh any risks.

The FDA requires drug manufacturers to demonstrate strong evidence of safety and efficacy from 1-year phase 3 clinical trials in over 1,000 patients. In the context of an anti-obesity drug, the efficacy is defined as either a placebo-subtracted weight loss of at least 5% at 1 year (a criteria also adopted by the European Medicines Agency [EMA]), at least 35% of patients receiving the anti-obesity drug exhibiting a weight loss of at least 5% of their baseline body weight or a proportion of patients roughly double that of the placebo group to lose [18].

The potential risk of any drug is partly dependent on the severity and burden of the disease or condition itself. If a drug carries a high risk of serious adverse events and is indicated to treat a minor itch, then intuitively, it would likely be considered inappropriate for use. However, if the drug carries a high risk of serious adverse events yet is used to treat a disease that is life-threatening, then the decision is much more finely tuned. A multitude of factors dictates whether or not a drug is considered acceptable in its safety and efficacy, and these are evaluated by respected experts in each disease area.

How safe are GLP-1 receptor agonist drugs, like Semaglutide? 

The most common Semaglutide associated side effects are gastrointestinal related, including nausea, diarrhoea, vomiting and constipation. However, in the STEP-1 clinical trial, these were mostly mild to moderate in severity, transient, and resolved without discontinuation of treatment. Overall, similar percentages of participants in the Semaglutide and placebo group reported adverse events (89.7% and 86.4%) respectively [16].

Serious adverse events were reported in 9.8% and 6.4% of Semaglutide and placebo participants, respectively with more participants in the Semalutide group than in the placebo group (7.0% vs. 3.1%) discontinued treatment attributable to adverse events (mainly gastrointestinal events) (4% difference between groups) [16].

The safety profile of Semaglutide is consistent with other drugs in the GLP-1 receptor agonist class. The transient nature of these side effects seems to be a consistent theme, which means the longer the duration of exposure to the drug, the less pronounced the side effects are, or complete discontinuation of the side effects is present. As can be seen below with Liraglutide, the average nausea related side effects experienced by Liraglutide slowly diminished over the 52-week duration [19].

The benefits of Semalutide and other GLP-1 receptor agonists could be profound for a large proportion of the obese population, and in terms of its safety, there does not seem to be any major red flags that would warrant a dismissive reaction. In light of the growing need for medicinal interventions to treat obesity, it is of no surprise to see the FDA approve Semalutide as an anti-obesity medication, adding an extra weapon to fight the obesity epidemic. In my opinion, it seems unusual that some within the nutrition community (whose overarching aim should be to put the health and wellbeing of any patient first), find the idea of medicinal therapies to treat obesity wrong. Of course, it will always be down to the clinical judgment of physicians to decide whether or not they are appropriate for each individual patient, but face-value dismissal on the basis of an obesity treatment being a drug is wrong.

''But you're not fixing the underlying problem, bad diet and lifestyle!''

This is true to an extent. Treating obese patients with pharmacological agents may not improve the food choices of the individual, or help with the deleterious effects of calorie-dense, highly processed food intake. However, increasing satiety and reducing motivation around food will likely reduce the consumption of these foods, therefore, reducing those deleterious effects. In my opinion, this common concern is irrelevant as behavioural/lifestyle modifications and pharmaceutical interventions are not mutually exclusive. Treating obesity through lifestyle interventions will always be recommended, and can nicely complement pharmaceutical therapies to produce an even greater effect on weight loss and health.

Is it wise to not treat patients at risk of heart disease with statins, or other therapeutic agents, because it is not fixing the underlying problem causing heart disease, namely bad diet and lifestyle? This rationale does not translate well when it is applied to other therapy areas. Many conditions are a result of poor lifestyle factors but yet readily treatable with pharmacological therapies, with the use of such widely accepted and appreciated, so why should obese be treated any differently unless there is a good reason to do so?

Final thoughts:

Obesity is a ubiquitously misconceived, and deleterious condition that has sadly become ignominious in today's society. There is a multitude of factors that explain why many are more prone to obesity than others, and it's certainly not a result of poor willpower or laziness. Nonetheless, obesity is a serious condition that increases the risk of a wide array of comorbidities, such as diabetes, heart disease, and cancer [20,21,22]. The health benefits of lowering and sustaining a healthy weight are difficult to overexaggerate, and one should keep in mind the seriousness of such a condition when exploring possible interventions.

With the failure of holistic lifestyle approaches to tackle the obesity epidemic, one has to explore alternative options through the aid of pharmacotherapy. However, even with highly effective pharmacotherapies, it is likely that further, and more structural changes in society are needed to make a meaningful population impact. The swift change in our food environment to an abundance of highly palatable easy access and cheap food is likely a major contributing factor to the obesity epidemic. I believe a much larger emphasis and resources are needed on structural interventions in society to make the desired impact, but there is little doubt that newly developed anti-obesity drugs can help considerably.

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