Can popping a PILL EVER beat OBESITY?

Safe and effective weight-loss pills have been a medical Holy Grail for decades. Now, launching the Mail’s Good Health for Life month, we ask the experts...

TACKLING obesity is ‘one of the greatest longterm health challenges’ this country faces, the government announced recently as it launched a new strategy to address it. and when it unveiled its own obesity plan in 2018 the Scottish government said ‘being overweight or obese is now the norm for Scottish adults’.

The figures speak for themselves: about two-thirds of adults in the Uk are overweight and, of these, half are obese. it is known that excess fat is a risk factor for serious conditions including cardiovascular disease, type 2 diabetes and some cancers.

and as we have seen during the covid-19 pandemic, patients who are obese are more vulnerable to serious infection and death.

One of the best steps towards reducing all this — cancer rates, cardiovascular risks and even outcomes from infections — is to address weight problems, says Professor Jason Halford, head of the school of psychology at the University of leeds and president elect of the European association for the Study of Obesity.

Yet weight reduction is not central to public health strategies for many of the conditions it can help, such as type 2 diabetes and cancer, adds Professor Halford — no one is setting out exactly what target weight people should be. ‘Weight management should be at the centre of what we are doing for these conditions,’ he says.

The standard advice is to adopt healthy lifestyle changes, such as cutting back on sugary, high-fat foods and exercising more. But this is too simplistic, says John Wilding, a professor of medicine who leads clinical research into obesity, diabetes and endocrinology at the University of liverpool.

‘Obesity is caused by complex factors. Even if someone is motivated to lose weight, often people are good at “defending” the weight they have, due to physiological processes. The body may slow metabolism and increase hunger signals, for example.’

One theory is that this is because obesity is not an evolutionary problem, whereas a lack of food was — so essentially our bodies are programmed to retain weight.

Professor Wilding adds: ‘Furthermore, even if you are successful with diet and exercise, most people will regain that weight and sometimes gain more, as the approach they have taken is not sustainable.

‘instead, people with obesity need help in the form of psychological support, drugs and sometimes surgery to address all the complex causes and achieve longterm, meaningful weight loss.’

WAS FATBUSTING PILL A PIPE DREAM?

YET the drug options for patients struggling with their weight are limited, says Professor Jonathan Pinkney, a specialist in obesity treatment. ‘We are still a long way off finding the Holy grail.’

it has long been assumed that any solution would take the form of a pill. currently, the only weightloss drug widely available on the nHS is orlistat, which prevents about a third of the fat from the food you eat being absorbed.

Yet orlistat (available on prescription and non-prescription), which was launched in the Uk in 1998, is ‘only modestly effective’, says naveed Sattar, a professor of metabolic medicine at the University of glasgow.

‘it causes weight loss of 2-4kg, which is often insufficient to lessen risks meaningfully. it causes gastric side-effects such as fatty stools, which many people can’t tolerate for long. Once they come off the drug, they often regain weight.’

But experts believe an effective obesity drug may be on the horizon. One of the frontrunners mimics a hormone in the gut called glucagon-like peptide-1 (glP-1), which controls appetite. a form of the drug called liraglutide (brand name Victoza) is approved in the Uk for type 2 diabetes and patients who take it report weight loss. Trials are continuing to see if it is effective in obesity specifically.

This approach — tackling gut hormones — is a radical departure from the previous thinking about obesity drugs, which has had spectacular failures.

The drug rimonabant, hailed as a ‘wonder pill for slimmers’ when it was first approved, was withdrawn in 2008 due to concerns that it caused depression and suicidal thoughts. it targeted cannabinoid receptors in the brain linked to appetite but also blocked receptors in other brain areas linked with mood.

Sibutramine, which enhanced satiety (feeling full) by attaching to brain receptors, was suspended in 2010 after patients were found to be at higher risk of blood pressure problems and heart attacks.

AFTER FALSE DAWNS, NEW PROMISE

‘THE trouble with medicines so far is that a lot of them target brain receptors that are ubiquitous, so there have been serious sideeffects,’ explains Dr Rob andrews, an associate professor of diabetes at the University of Exeter. ‘The appetite areas in the brain use similar hormones and receptors to the cardiovascular and mood centres, so it has been a challenge to find the right balance.’

This is where new obesity drugs show promise, he adds, because they target gut-signalling pathways instead. ‘We are learning from the benefits of surgery and why it works so well to try to find new drugs that target the same gut mechanisms,’ he says.

Over the past four decades, one treatment has emerged as the most effective for obesity: bariatric surgery. The procedures, which include gastric bands, gastric bypass and sleeve gastrectomy (where a large part of the stomach is removed), make you feel fuller sooner. There is also evidence they permanently reduce levels of hunger-stimulating hormones. But surgery is not suitable for every patient who is obese and is reserved for ‘complex’ cases, says Professor Wilding. Patients can be considered for NHS bariatric surgery if they have a BMI of 40 or more, or a BMI of between 35 and 40 and an obesity-related condition such as type 2 diabetes.

Yet less than 1 per cent of the patients in the Uk who are eligible receive bariatric surgery. ‘This is against all evidence that shows how useful surgery can be for those who are severely obese,’ argues Professor Francesco Rubino, chair of metabolic and bariatric surgery at king’s college london.

DRUGS THAT MIMIC SURGERY BENEFITS

BUT lessons can be learnt from the effectiveness of weight-loss surgery, experts say, and may pave the way for better drugs for obesity.

‘Many of the benefits of surgery come not from physically limiting the amount of food one can eat but from the changes these operations induce in the physiology of the gut,’ says Professor Rubino.

‘Multiple compounds, hormones and bile acids we thought were only involved in digestion are actually part of appetite mechanisms that, through surgery, we block or change. as we understand more

about them, they can be exploited to find new treatments.’

Bariatric surgery seems to ‘enhance’ signals from the intestine that tell the brain we are full, adds Professor Wilding. ‘So now medicines are starting to mimic normal gut responses to hunger rather than acting centrally on the brain.’

This is how the type 2 diabetes drug liraglutide works. It effectively ‘talks’ to the brain and helps control appetite.

Marketed as Saxenda and given as a daily injection, it was launched in the UK in January 2017, licensed for patients with obesity as an add-on to diet and exercise — but it has not yet been approved for use on the NHS.

‘Trials have shown liraglutide can lead to an extra 6kg in weight loss above what diet and exercise alone can achieve,’ says Professor Wilding.

Liraglutide affects appetite signalling and means patients get full quicker and stay fuller for longer, adds Dr Andrews.

‘There is also some evidence it dampens inflammation in the brain that is thought to affect appetite signals and worsen the impact of obesity. Evidence from trials in type 2 diabetes patients show GLP-1 drugs can protect against cardiovascular disease and stroke, which is hugely important for those with obesity.’

Professor Pinkney describes liraglutide as ‘the most promising drug we have seen for a long time’, adding: ‘We would like to see it approved for NHS use’.

The National Institute for Health and Care Excellence is due to review whether liraglutide should be used on the NHS today (and will publish its decision in November, according to its website), having previously rejected it on grounds of cost- effectiveness — a month’s supply costs £196.20; by comparison, orlistat costs £18.05.

Dr Andrews hopes the drug will be approved for use in specialist clinics for people with a BMI above 35, which would make its use more cost-effective.

A similar drug, semaglutide, given as a weekly injection, may be preferable as it is more convenient for patients and leads to even more weight loss — up to 15kg after a year — adds Professor Wilding. It is approved for type 2 diabetes (with weight loss as a side-effect) and is in trials at higher doses for obesity.

TRIPLE ACTION JAB FOR WEIGHT LOSS

BUT rather than relying on a single medicine, experts are exploring whether they can bolster the results from GLP-1 drugs by combining them with others that target different hormones in the gut.

‘There are a number of other gut hormones that have been identified from bariatric surgery as beneficial,’ says Professor Wilding. ‘We could one day create a similar effect to surgery by targeting multiple hormones with medicines — but it will be a few years yet.’

One such drug is tirzepatide, which is still undergoing latestage trials run by the manufacturer Eli Lilly. This drug targets GLP-1 as well as another hormone, glucose-dependent insulinotropic polypeptide (GIP), which is released by the small intestine to control digestion.

People who took tirzepatide reported significantly more weight loss in early trials compared with those who took just a GLP-1 drug, reported The Lancet in 2018. ‘Targeting two or more hormones in the gut should help people lose 10 to 15 per cent of their excess bodyweight and trials are testing their safety,’ says Professor Sattar.

‘It is at this level that we make significant advances towards treating or reversing the complications of obesity, as well as improving quality of life.’

There may even be the potential to create a triple-action drug that targets GLP-1, GIP and glucagon, a hormone which controls blood sugar and is thought to burn fat.

In a study last year, researchers at Imperial College London targeted these three gut hormones in an infusion treatment and found that when it was given for up to 12 hours a day for 28 days, patients achieved better

blood sugar control than they would have after bariatric surgery and a favourable effect on bodyweight, the journal Diabetes Care reported. the researchers said the proof-ofconcept study suggests this approach may have advantages even over bariatric surgery.

glP-1 drugs can cause side-effects such as vomiting and abdominal pain. More rarely, there have been reports that they may cause pancreatitis (they work by stimulating the pancreas) and even pancreatic and thyroid cancers, but there is no conclusive evidence, says Dr Andrews. ‘Nevertheless, we wouldn’t prescribe these drugs to patients we know are at risk of these conditions.’

IS INFLAMMATION WHAT’S MAKING PEOPLE FAT?

OtHer evidence suggests obesity may be linked to inflammation, and that tackling the latter may help with obesity complications and even boost weight loss.

fatty tissue increases ‘inflammatory’ compounds which may lead to a constant, ‘chronic’ inflammation that can damage blood vessels and contribute to complications such as heart disease and cancer.

Some researchers are looking at whether blocking inflammatory responses may reduce the impact of obesity.

‘Some glP-1 drugs that lead to weight loss seem also to target inflammation directly or indirectly, and that may be one reason why they reduce complications such as heart attacks,’ says Professor Wilding.

But it’s difficult to know which comes first, adds Dr Andrews: ‘As fat cells get bigger, do you get inflammation that affects the brain and other organs? Or does someone’s diet directly cause inflammation in the brain, which creates changes that then contribute to obesity and inflammation elsewhere? regardless, inflammation is involved and could be a target for obesity medication.’

this is the principle behind trials of an antiinflammatory drug invented in the 1980s for asthma as a treatment for obesity. in a study in mice, U.S. researchers found that the drug, amlexanox, blocked proteins which stop them burning calories. giving it to obese mice made them lose weight. When diabetes patients were given the drug, it improved their blood sugar levels and some also lost fat around the liver, reported the journal Cell Metabolism in 2017. A trial is now under way at the University of Michigan, testing it on patients with obesity and type 2 diabetes.

NOT EVERYONE WILL RESPOND EQUALLY WELL

exPertS agree that identifying which patients would benefit from any treatment is key to its success. Professor Halford explains: ‘Obesity is not just about people having poor appetite control or eating unhealthily.

‘it is associated with genes, depression and life events. there is no point in giving a patient a drug to lose weight if the reasons for their weight gain aren’t addressed.

‘At some point they will also need to stop the drug and they will need support for that, too. Any potential drug must be given as part of a holistic approach with dietitians, psychological support and proper longterm monitoring.’