Losing weight – and not putting it back on – is about much more than willpower. Nina Notman reports on the drugs trying to penetrate the complex metabolic web of hunger and satiety
The obesity epidemic shows no signs of abating. In 2016, it was reported that 26% of UK adults are affected by obesity – that is, their body mass index was 30 or above. In the US, the figure was almost 40%. The same Organisation for Economic Co-operation and Development (OECD) report predicted that proportions would continue to balloon globally, reaching 35% in the UK and 47% in the US by 2030.
In the modern world, it is easier than ever to eat more calories than we burn off. We are constantly bombarded by marketing messages encouraging us to eat, more often than not unhealthy food, while our lifestyles have grown ever more sedentary.
Despite our expanding waistlines, the prevailing societal assumption is that regaining control of our weight requires nothing more than a bit of willpower. But this is not a view supported by science. Decades of fundamental biological research into why so many of us struggle to both lose weight and then keep it off has revealed that our bodies are rigged up to rally against weight loss.
Weight regain isn’t just people falling off the wagon
A complicated web of hormones and other biochemical factors is now known to control our body’s hunger, satiety – how full we feel – and food reward systems. The details of this web are still being figured out, but it is well established that multiple processes work together like a thermostat to maintain our weight. When we lose weight, these systems act to push our appetite up and our metabolic rates down. This control system works in both directions, but resists weight loss more vigorously than weight gain.
‘Weight regain isn’t just people falling off the wagon and going back to being lazy or gluttonous, it’s actually the body fighting against that weight loss to take us back to where we were before,’ explains Matthew Capehorn, a doctor and clinical manager at the Rotherham Institute for Obesity in the UK.
The first weight-loss pills
Long before this physiological web was uncovered, people sought fast fixes for weight loss. So-called slimming pills have been in existence for over a century. In the early 1900s, for example, dieters were encouraged to swallow tapeworm eggs. The idea was that the worms – once hatched – would consume food in the intestines, reducing calorie intake. And the 1930s saw industrial chemical and pesticide 2,4-dinitrophenol peddled as a weight-loss tool. It was eventually banned, but not before numerous deaths.
Since then a number of other slimming pills have also been withdrawn from the market following safety concerns. The most high-profile ban was that of Fen-Phen, a combination of the amphetamine analogues fenfluramine and phentermine, in the late 1990s. The fenfluramine component was linked to heart-valve damage. In 2000, Europe also banned the use of phentermine alone, a decision that caused significant controversy. In the US, phentermine remains the most commonly prescribed antiobesity drug.
Phentermine is an appetite suppressant, thought to modulate catecholamines in the hypothalamus’s satiety centre. Weight-loss drugs past and present work in one of three ways: modulating appetite, boosting metabolism or blocking fat absorption. Orlistat, for example, the only antiobesity medicine currently approved by the UK’s National Institute for Health and Care Excellence (Nice), prevents around a third of the fat in food from being absorbed by the body. ‘Orlistat has been around for 20 years now and is a good drug, but only has minor effectiveness,’ explains Capehorn. It also causes unpleasant gastrointestinal side effects. Orlistat is also available at a lower dose, over the counter, under the brand name Alli.
The new-generation drugs
The complicated web of biochemicals that regulate hunger and body weight offer a bonanza of possible biological targets for targeting obesity. And since 2012, four new antiobesity medications have hit the market, each targeting different pathways. This brings the total of medications approved for treating obesity in the US to six. None of these newer drugs has yet been approved for use on the NHS.
Serotonin-receptor agonist Belviq (lorcaserin) was the first to be approved, in June 2012. The neurotransmitter serotonin, or 5-hydroxytryptamine (5-HT), has numerous roles in the body, including in appetite control. Belviq preferentially binds to the 5-HT2C receptors, thus avoiding safety issues found with previous, less specific, serotonin-targeting antiobesity drugs. But Belviq’s manufacturer, Arena Pharmaceuticals, announced in May 2013 it was withdrawing its application for European Medical Agency (EMA) approval. The company stated at the time that it would not be able to address all of the EMA’s safety concerns within the application timetable.
July 2012 saw an FDA thumbs-up for Qsymia, a combination of two already-approved drugs – phentermine and topiramate, an antiepileptic. Topiramate’s exact mechanism in weight-loss is unknown, but it’s thought to have several relevant cellular targets including the gamma-aminobutyric acid (GABA) receptors. As well as suppressing appetite, topiramate is thought to boost metabolic rate. The EMA refused Qsymia’s manufacturer, Vivus, permission to market this drug in Europe in October 2012, citing safety concerns linked to its phentermine component.
Another combination antiobesity drug hit US pharmacy shelves in 2014 – Contrave, comprising naltrexone and bupropion. Both components were already approved for other indications. Naltrexone is an opioid receptor antagonist, used for treating alcohol and opioid dependence. Bupropion is a dopamine–norepinephrine re-uptake inhibitor, approved for treating depression and helping people quit smoking. This combination is also authorised by the EMA as an antiobesity medication under the brand name Mysimba. In December 2017, however, it was turned down in the UK by Nice. The committee said that although clinical evidence showed Mysimba was more effective than lifestyle measures alone, its long-term cost effectiveness was unknown. ‘Their argument is that if a patient loses weight, it isn’t necessarily guaranteed that you’re less likely to develop the diabetes and the heart disease and therefore save the NHS money,’ explains Capehorn. Mysimba, produced by Nalpropion Pharmaceuticals, is available on private prescription in the UK, however.
Private clinics in the UK, such as Capehorn’s in Rotherham, also prescribe Saxenda (liraglutide), a glucagon-like peptide-1 (GLP-1) receptor agonist, approved in the US in 2014 and the EU in 2015. Saxenda is currently being assessed by Nice for potential availability on the NHS.
In Phase III clinical trials
GLP-1 is an exciting target in the eyes of most obesity researchers. This peptide is one of many signalling hormones naturally produced by the intestines in response to food, and has been shown to perform a variety of functions. In the brain, GLP-1 acts to increase satiety and lower appetite; Saxenda has been shown to mimic this natural response.
GLP-1 also helps to lower blood sugar levels. ‘The first indication that GLP-1 agonists were approved for was treatment of type 2 diabetes,’ explains Marianne Grønning, corporate project vice-president for obesity at Novo Nordisk, Saxenda’s manufacturer. A different dose of liraglutide, marketed by Novo Nordisk as Victoza, has been approved for treating type 2 diabetes since 2010. Now, Novo Nordisk is trialling another of its GLP-1 diabetes drugs – semaglutide – as an antiobesity medication.
In June 2017, the company reported some very promising Phase II results. ‘The potential for weight loss that we saw in the study was about double what we know is possible with liraglutide,’ says Grønning. ‘After one year of treatment, the participants who were assigned to the highest dose had lost a mean of 13.8% of their body weight. In addition, two-thirds of participants lost at least 10% of their body weight, compared to 10% of the placebo group.’ Semaglutide in now in Phase III trials, with results expected in 2020. Other pharma companies including AstraZeneca, Sanofi-Aventis and Eli Lilly are also looking at whether their GLP-1 diabetic drugs could also be used against obesity.
Also in Phase III clinical trials is setmelanotide, a melanocortin 4 receptor (MC4R) agonist under development by Rhythm Pharmaceuticals, based in the US city of Boston. Unlike the GLP-1 analogues, setmelanotide is targeted towards a small proportion of individuals with obesity – those with certain defects in the MC4R pathway. ‘Our approach at Rhythm is targeting genetic disorders of obesity,’ explains Murray Stewart, chief medical officer at Rhythm.
Defects in the MC4R pathway can result in severe hunger and decreased metabolism, which presents itself as severe obesity starting in childhood. ‘Targeting the pathway results in a significant reduction in hunger, that leads to decreased food intake to cause significant weight loss with some additional effects on resting energy expenditure,’ says Stewart.
In June 2018, Rhythm completed enrolment of patients with pro-opiomelanocortin (POMC) deficiency and leptin receptor (LEPR) deficiency in Phase III trials with setmelanotide. ‘We’re in a year-long, 10-patient Phase III study with POMC and a 10-patient LEPR study,’ Stewart says. The company is planning regulatory filings, in both the US and EU, by early 2020.
In December 2018, Rhythm enrolled its first patient in a third Phase III trial, this time evaluating setmelanotide in Bardet-Biedl syndrome (BBS) and Alström syndrome. ‘Our aim is to get up to 30 patients enrolled in the joint BBS and Alström study,’ says Stewart. He hopes to then file that indication in 2021.
In the lab
Another area of intense activity is the possibility of mimicking the actions of the growth differentiation factor-15 (GDF-15) protein. About a decade ago, it was realised that cancerous tumours that caused significant body weight loss were producing high amounts of this protein. ‘GDF-15 is a circulating factor that can profoundly reduce food intake,’ explains Randy Seeley, an obesity researcher at the University of Michigan in the US.
Pharmaceutical companies were quick to see the potential here. ‘In 2017, four groups almost simultaneously revealed the receptor for which GDF-15 acts upon,’ says Seeley. Janssen, Eli Lilly, Novo Nordisk and a collaboration between NGM Biopharmaceuticals, Merck and XTAL BioStructures all published animal data showing that GDF-15 acts on the glial cell-derived neurotrophic factor receptor alpha-like (GFRAL) receptor.
This receptor is located on a couple of hundred neurons in the brain stem, which is on the body side of the blood–brain barrier. ‘It’s got two distinct advantages. You don’t have to figure out how your drug will get across the blood–brain barrier and, because it’s such a small population of neurons, you have less worry that you’re going to cause untoward side effects,’ explains Seeley.
Animal studies of various GDF-15 analogues are ongoing, but so far none has yet reached clinical trials. ‘We’re trying to understand the biology of this system as a way to help us understand about how useful this will be as a therapeutic,’ says Seeley. But the signs so far are good. Seeley, for example, recently collaborated with Novo Nordisk to trial GDF-15 analogues in combination with the approved drug liraglutide in mice. ‘We saw weight loss that’s much greater when we gave the two together than when we gave the two individually,’ he explains.
Another hot research area is the possibility of using brown fat as an antiobesity therapeutic. The two main types of fat tissue in mammals are white fat and brown fat. White fat cells capture fats from the blood and store the excess energy as triglycerides. In adult humans, the vast majority of our fat cells are white. Brown fat’s role is to generate heat without the need for muscle-shivering, and it is more prevalent in babies. ‘The average amount of brown adipose tissue in an adult human is about 300g,’ explains Shingo Kajimura, a biomedical scientist at the University of California, San Francisco in the US. ‘Its brown colour comes from the iron in the mitochondria.’
Mitochondria are the energy powerhouses of cells, converting chemical energy from food into ATP (adenosine triphosphate) and heat. Recent fundamental research has shown, however, that brown fat plays a much larger role in body weight management than simply burning off chemical energy. That explanation is ‘too simplistic’, says Kajimura. ‘There are many mechanisms involved and one, proposed by ours and other groups, is that brown fat secretes hormones that talk to other organs such as the muscle, liver and brain.’
Extensive efforts to harness the brown fat as an obesity treatment have been undertaken, ‘but nothing so far has reached clinical trials’, Kajimura says.
Matching up to bariatric surgery
Today, bariatric (weight-loss) surgery – with appropriate lifestyle changes – is widely considered as the most effective long-term tool against obesity. ‘Bariatric surgery is the best treatment that we have for obesity,’ says Caroline Apovian, professor of medicine and obesity researcher at Boston University in the US. ‘The meds give you up to 10% weight loss; surgery offers 33% kept off for a long time.’
‘The idea that weight-loss surgery works by making your stomach smaller, making it physically difficult to eat and causing malabsorption, is very outdated at this point,’ explains David Cummings, bariatric surgery specialist at the University of Washington in Seattle, US. Instead, it impacts multiple components of our body’s hunger, satiety and food reward systems. In doing so, it manages to override the increase in appetite and decrease in metabolic rate normally seen during weight-loss. ‘Because of these and many other benefits, this type of operation is increasingly being referred to as metabolic surgery,’ says Cummings. ‘Bariatric surgery targets lots of different pathways, with the drugs you only target one or two pathways,’ explains Apovian.
The nice thing about surgery is you usually only have to do it once
To see the levels of weight loss with drugs that is achieved with bariatric surgery, it is widely accepted that multiple pathways will need to be targeted simultaneously. ‘There’s been this concept in the field for a while that, because of the multifaceted nature of biocontrol, any one agent is not likely to be able to overwhelm the system and create huge effects,’ says Cummings.
This poses a conundrum, because regulatory bodies don’t like approving combinations of two new drugs simultaneously. (Qsymia and Contrave are combinations of previously approved entities.) ‘Imagine you have new weight loss drugs A and B that work on two different mechanisms and together are highly powerful. If neither is effective enough to be FDA-approved alone, the combination will never be approved,’ says Cummings.
‘Combining the GLP-1s that are starting to be approved with other appetite suppressants that have different mechanisms of action in the brain is probably going to be the wave of the future,’ predicts Apovian. She adds that combinations of antiobesity drugs are already prescribed in clinics such as hers. ‘We don’t publish this because you need money to do a good study and companies are not willing to fund studies on drugs that aren’t theirs.’
The other question hanging over antiobesity drugs is how good they are at maintaining weight loss long term. The evidence suggests that our bodies continue their fight to regain lost pounds long term. ‘Anything that’s going to result in an effective long-term treatment for obesity has to not only succeed in achieving weight loss, but also in blocking the adaptive responses that would drive recovery of lost weight,’ says Michael Schwartz, Cummings’ colleague at the University of Washington.
‘The nice thing about bariatric surgery is you usually only have to do it once and the effect is sustained in most people for a long period of time,’ he adds. ‘To get a similar effect from drug regimens, you would presumably have to continue to be exposed to it long-term.’
In the future, will obesity be treated as chronic disease with lifelong medication regimes used to manage it? The concept of treating obesity as a disease has many opponents, so only time will tell if the escalating obesity crisis will eventually tip the scales away from viewing obesity as a simple lifestyle choice.
Nina Notman is a science writer based in Salisbury, UK