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Pills for the pounds: A primer for drugs on the weight list




Defined as having a body mass index (BMI) of above 30, one-fifth of Malaysia’s adult population is considered obese (World Obesity Federation, 2020). While it is tempting to not judge one’s health by the body, there is plenty of evidence showing that obesity poses a public health problem by increasing the risk of chronic conditions such as cardiovascular disease, type 2 diabetes, cancer, and even complicates management of diseases such as Covid-19 (Müller et al., 2021). With that being said, lifestyle and behavioural intervention alone shows moderate efficacy in treating obesity. Fortunately, several anti-obesity medications (AOMs) have been developed and some are very effective nonetheless.


Figure 1: Obesity-associated health conditions. Image taken from “Anti-obesity drug discovery: advances and challenges” (Müller et al., 2021)


As of writing this article, many medications have been proposed to be effective in combating obesity, but only 2 have been FDA-approved for rare monogenic obesity syndromes (obesity caused by mutations in just one gene), whereas only 6 are still approved for polygenic obesity (caused by mutations in many genes). I said still as there have been drugs that have been approved but taken down after, such as fenfluramine.


Physiology of weight gain


Before discussing the AOMs, we have to understand some basic physiology of weight gain. In the simplest terms, weight gain/loss is determined by energy balance. By eating food, we are consuming energy, and by simply existing and living, we are expending energy. If we consume more than we expend, we gain weight, and vice versa (Hill, Wyatt and Peters, 2013).


Figure 2: Simplistic diagram of the energy balance theory of weight loss. Image taken from Ace Fit Club Personal Training.


Minor players in AOMs


The oldest AOM still approved today is orlistat, having been approved back in 1999. Orlistat functions by inhibiting an enzyme known as lipase in our gastrointestinal tract that helps breakdown fat for absorption. By inhibiting lipase, less fat is absorbed from our meal, and hence less energy is ingested (Bansal and Al Khalili, 2020). A meta-analysis of 33 randomized controlled trials showed that although orlistat did cause more weight loss relative to a control group (not always placebo), it was very minimal (~2.7 kg more) (Sahebkar et al., 2017). Another large scale meta-analysis also showed that treatment with orlistat reduces LDL cholesterol and improves glucose metabolism (Khera et al., 2018). Due to its mechanism, it is proposed that orlistat could work better in conjunction with a high-fat diet, but that still remains to be seen. However, the fact remains that the decreased absorption in fats often result in diarrhoea and fatty stool, which may be accentuated on a high-fat diet (Bansal and Al Khalili, 2020).


Figure 3: Mechanism of action of Orlistat. Image taken from Arshine.


Another FDA-approved AOM is a combination of phentermine and topiramate. Phentermine is a sympathomimetic, ie it stimulates the sympathetic nervous system and increases energy expenditure. Topiramate on the other hand stimulates satiety through the central nervous system by increasing activity of inhibitory neurotransmitters (Johnson and Quick, 2021). This combination has been shown to reduce body weight modestly by around 7.7 kg more when compared to weight loss in the placebo group, while improving glucose metabolism and blood pressure (Lei et al., 2021). As a result of its centrally-acting mechanism, this combination has side effects that include sleep disorders, cognitive impairment, headaches, and dizziness (Johnson and Quick, 2021).


FIgure 4: Phentermine/topiramate (Qysmia) effects on the central control of appetite. Image taken from Dr. Richard Lipman MD.


Yet another combination of drugs that is FDA-approved for weight loss is naltrexone and bupropion. Individually, naltrexone blocks the mu opioid receptors which help manage addiction and decreases food intake while bupropion inhibits reuptake of dopamine and norepinephrine which helps induce satiety (Sherman, Ungureanu and Rey, 2016). They are thought to work synergistically to help with weight loss. From a meta-analysis of clinical trials, this combination only causes an additional 2.5 kg of weight loss compared to a placebo (Onakpoya et al., 2020). However, among the other medications discussed, this combination has one of the highest odds of adverse events, the most common ones being nausea, anxiety, and headaches (Khera et al., 2016).


Monogenic obesity


Before moving on to the 3 big boys, let’s talk about those two approved for monogenic obesity. POMC, PCSK1, and the leptin receptor are proteins highly involved in the central control of dietary intake. Congenital deficiencies in these proteins result in underactivation of the melanocortin-4 receptor (MC4R) and causes severe childhood-onset obesity (Ranadive and Vaisse, 2008). Setmelanotide, is a MC4R agonist (which means it activates MC4R) that has been shown to reduce body weight in those with obesity secondary to the deficiencies mentioned. The most common side effect of Setmelanotide is hyperpigmentation disorders, as MC4R also regulates skin pigmentation (Clément et al., 2020).


Metreleptin on the other hand, is a molecule that resembles leptin. In a study with 17 patients with generalised or partial lipodystrophy, metreleptin had extremely beneficial effects in many metabolic markers, including LDL-cholesterol, triglycerides, fasting glucose, etc (Grover et al., 2021).


GLP-1 receptor agonists


The next 3, liraglutide, semaglutide, and tirzepatide are a group of medications known as GLP-1 receptor agonists. Perhaps you all may have heard of semaglutide as Wegovy or Ozempic, and how it had been used by celebrities like Elon Musk to lose weight. However, before semaglutide, there was actually liraglutide. GLP-1 is an incretin hormone released by enteroendocrine-L cells when food is digested in the gastrointestinal tract and acts to slow gastric emptying, induce insulin release and increase satiety (Collins and Costello, 2023).


Figure 5: Effects of GLP-1 on various organs of the body. Image taken from Sydenham Clinic.


Funnily enough, all 3 of the medications were first approved for treatment of type-2 diabetes, and it was not until researchers realised that treated patients lost a bunch of weight that the 3 medications got approved for weight loss. Compared to semaglutide and tirzepatide, liraglutide seems to be underperforming, only resulting in weight loss of around 5.5kg more than placebo (Zhang et al., 2019). Semaglutide on the other hand boasted a 12.5% reduction in bodyweight in the trial that got it FDA-approved for weight loss, and has consistently showed ~10% more weight loss (or around 10kg) more than placebo (Gao et al., 2022). 


Tirzepatide is a little more special, being a GIP receptor agonist on top of a GLP-1 receptor agonist. GIP is also an incretin hormone, and similar to GLP-1 slows gastric emptying, increases insulin secretion, and insulin sensitivity (Willard et al., 2020). With its dual action capability, tirzepatide could potentially reduce bodyweight by 5-6% more than semaglutide’s highest dose, though this was an indirect comparison as direct comparison trials have not been done (le Roux et al., 2023). 


Figure 6: GIP and GLP1 can both contribute to better health outcomes. Image taken from “Tirzepatide: A Promising Drug for Type 2 Diabetes and Beyond”(Dutta et al., 2023).


More importantly, a recent study from the American Heart Association showed that semaglutide did in fact reduce cardiovascular disease outcome in addition to weight. Of course, these all not without side effects with GLP-1 receptor agonists most commonly causing nausea, and gastrointestinal side effects (A. Michael Lincoff et al., 2023).


Recently, we have gotten a new guest, retatrutide. Whereas tirzepatide was a double agonist, retatrutide is a triple agonist, a GLP1/GIP/GCGR receptor agonist. GCGR is a glucagon receptor and when stimulated seems to also produce a satiating effect and increases energy expenditure (Nason et al., 2021). This medication has yet to be approved, but a recent phase 2 trial shows as high as a 22% more weight loss compared to placebo (Jastreboff et al., 2023).


Figure 7: Efficacy of retatrutide. Image taken from “LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept” (Coskun et al., 2022).


With all that being said, this doesn’t mean that if you are obese, that you should only take these medications. Most of the trials, especially those involving the GLP-1 receptor agonists include the medication on top of lifestyle modification. The efficacy of AOMs also haven’t seem to exceed that of bariatric surgery which typically result in an almost 30% reduction in bodyweight (Maciejewski et al., 2016), but we’re getting closer by the day. Who knows, one day there may be no need to cut out our stomachs to lose weight. But for the time being, it is important that we stay optimistic but grounded so as to not make exaggerated claims. It is also vital that obesity be recognized as a chronic, degenerative disease, rather from just a lack of willpower, in hopes of destigmatizing obesity and allowing access to basic funding and clinical research for better development of AOMs.

 

Article prepared by: Jared Ong Kang Jie, R&D Director of MBIOS 2023/2024


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References


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