How the next weight-loss wonder drug could be a pill – and it may be cheaper with fewer side-effects

The race to develop drugs to combat obesity is gathering pace, with the newest treatments promising to cost less and come with fewer side-effects. It means that obesity is becoming a treatable illness, writes Jo Waters

Tablets that beat the results of weight-loss injections have produced 'absolutely remarkable' results

NEW, more effective weight-loss drugs may soon overtake the current blockbuster slimming injections Ozempic and Wegovy.

The good news is these new drugs not only have fewer gastric side-effects, but some of them also come as pills, rather than having to be injected.

Wegovy (generic name semaglutide) can help obese people lose up to 15 per cent of their weight, and when it was launched in the United States for weight loss in 2021 it was seen as a breakthrough in tackling the growing global obesity and type 2 diabetes epidemics.

Just last month, new data from a five-year trial of Wegovy suggested it could cut the risk of a heart attack or stroke in obese people with cardiovascular disease by a fifth.

Ozempic, another weekly injectable that contains the same active ingredient, semaglutide, is currently only available on the NHS as a treatment for type 2 diabetes, and not specifically weight loss.

But such is its effectiveness that some doctors do prescribe it for obesity, with a private prescription costing around £300 a month.

In March, the National Institute for Health and Care Excellence (Nice) approved the use of Wegovy with diet and exercise as part of NHS specialist weight-management services.

It's available to people with a BMI of 35 and above who also have a weight-related condition such as high blood pressure, pre or type 2 diabetes or sleep apnoea.

Those with a BMI of 30 to 34 are eligible, too, if they also have a weight-related health condition and meet the criteria for referral to a specialist weight-management service.

But both these ground-breaking drugs have to be self-administered weekly, using an injection pen, and side-effects include nausea, diarrhoea and constipation.

There are reportedly two dozen second-generation weight-loss drugs in development that aim to improve on the benefits, and have fewer side-effects.

One is retatrutide, a weekly injection which, during clinical trials, led to an average 24 per cent weight loss (or 58lb in weight) in 48 weeks, according to results published in the New England Journal of Medicine in June.

This is the biggest weight reduction achieved by any drug so far. Those on retatrutide all lost at least 5 per cent of their body weight and, crucially, at the end of 48 weeks, they were still losing weight, with no sign of a plateau.

Retatrutide also contains semaglutide, that works by mimicking a hormone called glucagon-like peptide 1 (GLP-1), which is released in response to food and reduces the appetite, and slows stomach emptying, so you feel full for longer.

But retatrutide targets two other hormone receptors as well as those for GLP-1: these are GIP and glucagon. All three have the net effect of reducing appetite.

Obesity expert Giles Yeo, a professor of molecular neuro-endocrinology at the University of Cambridge, said that the retatrutide results were "absolutely remarkable".

"The results caused quite a stir at the American Diabetes Association meeting in San Diego in June, as the weight loss achieved is approaching the 30 per cent figure we get in patients who've had bariatric surgery [such as a gastric bypass]."

The retatrutide trial was a phase 2 trial — i.e. a small study that looked at safety and efficacy.

"If these findings hold up in phase 3 studies [where the drug is trialled in a larger group and compared with a placebo], retatrutide could be an option for people who are very obese who don't want surgery and would prefer an injection," says Professor Yeo.

"These drugs all have the same mechanism of mimicking hormones that control appetite, but retatrutide goes after three hormone receptors instead of one.

"We don't know the exact mechanism yet, but we think this combined approach may be more effective as the brain is getting these messages in bulk."

This triple-whammy, says Professor Yeo, convinces the brain that the gut is full when it isn't, "so people eat less".

And because it targets three hormone receptors, he says, it may mean the amount of each active ingredient could be reduced, potentially lowering side-effects compared with existing GLP-1 mimickers. Although retatrutide has similar gastric side-effects to semaglutide — mainly constipation, diarrhoea and nausea — the recent trial showed they were less severe.

Orforglipron is another new drug which works in a similar way — but its big advantage is that it comes as a tablet.

In trials, it led to average weight loss of 14.7 per cent of body weight in nine months, according to results in the New England Journal of Medicine in July. This is comparable to Wegovy.

Scientists developed weight-loss drugs initially as injections to avoid the ingredients being destroyed by stomach acid, says Professor Yeo.

"Lots of people may prefer taking a daily pill to an injection, especially if they are needle-phobic; others may prefer a once-a-week treatment. Pills will be cheaper to produce, too."

(Injections can cost around £300 a month privately.) A rival daily pill, called Rybelsus, is an oral version of Ozempic, with the same active ingredient, semaglutide and is approved for treating type 2 diabetes in the UK.

Although it's not a weight-loss drug, people do lose weight taking it; one study found up to 8lb in six months, depending on the dose.

Meanwhile, HU6 — a pill being developed by US firm Rivus Pharmaceuticals — appears to yield similar results to GLP-1 drugs, but works in a different way.

It's the first in a new class of weight-loss drugs called controlled metabolic accelerators, which harness a natural process in mitochondria, the ‘battery' in our cells, to increase the breakdown of fat and sugar and increase resting energy expenditure.

The next generation of medicines could be on the market within a couple of years, says Professor Yeo.

"All these drugs are giving overweight and obese people more options, and obesity is becoming a treatable illness," he adds.

"If you take Ozempic, for instance, all you're doing is changing one hormone in your body a little bit. What this tells us is that obesity is not some internal moral failing; it's a hormonal problem."

However, Professor Yeo stresses that weight-loss drugs will work only while you're taking them, and that you'll regain your appetite when you stop.

And he says more long-term safety data is needed: "Nice has approved Wegovy for two years' use for each patient, as we have only two years' safety data."

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