{"id":607100,"date":"2026-08-28T09:38:25","date_gmt":"2026-08-28T09:38:25","guid":{"rendered":"https:\/\/www.newsbeep.com\/ie\/607100\/"},"modified":"2026-08-28T09:38:25","modified_gmt":"2026-08-28T09:38:25","slug":"how-the-new-generation-of-glp-1s-will-change-weight-loss-forever","status":"publish","type":"post","link":"https:\/\/www.newsbeep.com\/ie\/607100\/","title":{"rendered":"How the new generation of GLP-1s will change weight loss forever"},"content":{"rendered":"

Today’s weight-loss drugs work by changing how much we eat. Ozempic, Wegovy and the like \u2013 the GLP-1s \u2013 reduce our desire to eat by interfering with the hormones<\/a> involved in blood sugar, appetite and feeling full.<\/p>\n

Put simply, they make it easier to stick to a diet.<\/p>\n

Cue the next generation of weight-loss drugs, which promise to do something radically different. Right now, drug companies are testing drugs that won\u2019t necessarily change how much food we eat, but rather what our bodies do with that food.<\/p>\n

These new drugs target the metabolic pathways governing how our bodies burn and store energy. Essentially, they alter the mechanics of the engine rather than how much fuel goes into it.<\/p>\n

Manufacturers say these new drugs could help people keep the weight off for longer while avoiding the muscle wastage that comes with GLP-1s.<\/p>\n

\u2018Could\u2019 is the key word here, though, because none of these drugs have been widely tested on humans \u2013 yet. Although they\u2019re now starting to make it into smaller trials.<\/p>\n

Will we see GLP-1s swept to the side as a new wave of weight-loss medications races to the market? Or is there a place in the world for both?<\/p>\n

Muscling in<\/p>\n

\u201cCurrent GLP-1 drugs like semaglutide [Ozempic and Wegovy] and tirzepatide [Mounjaro] are genuinely impressive. They can help people lose 15\u201320 per cent of their body weight,\u201d says Prof Maria Dalamaga<\/a>, who specialises in laboratory medicine and clinical biochemistry at the National and Kapodistrian University of Athens in Greece.<\/p>\n

\u201cBut they have some important limitations,\u201d she adds. One such limitation is that when people stop taking GLP-1s, their food intake usually shoots back up<\/a>, so any weight they\u2019ve lost returns quickly.<\/p>\n

The main problem, however, is that GLP-1-fuelled weight loss isn\u2019t just fat. About 25\u201340 per cent of it is \u2018lean mass\u2019 \u2013 muscle.<\/p>\n

It\u2019s a similar proportion<\/a> to what we see with conventional diets, because, like low-calorie diets, GLP-1s work by reducing our food intake. But why does this calorie-cutting approach waste away muscle?<\/p>\n

\"AnAn illustration of the molecular structure of semaglutide, superimposed over some fat cells – Image credit: Science Photo Library<\/p>\n

According to scientists, it\u2019s an energy-saving strategy we\u2019ve inherited from our ancestors. Muscle burns more energy than fat at rest, so shedding it may once have helped humans survive starvation.<\/p>\n

What this means is that losing weight while maintaining a healthy body composition is hard \u2013 our bodies would somehow have to override their default muscle-wasting programme. And that\u2019s what scientists making the next generation of weight-loss drugs are trying to do.<\/p>\n

\u201cI think we have to take our eye<\/a> off the magnitude of weight loss. That\u2019s not as important as quality [of weight loss],\u201d says Dr Mark Sleeman<\/a>, head of obesity, muscle and metabolism research at Regeneron Pharmaceuticals in New York, in the US.<\/p>\n

\u201cWe want patients to have quality weight loss, so [they can] decrease their fat, have proper storage of [their remaining] fat and preserve muscle.\u201d<\/p>\n

In 2022, Sleeman\u2019s team uncovered a link<\/a> between obesity and a signalling molecule known as Activin E. They found that people who made short versions of the Activin E protein \u2013 due to mutations in the Activin E gene \u2013 had a healthier body type and tended to store less fat around their waists and hips.<\/p>\n

\"CloseMost GLP-1s have to be injected weekly. It\u2019s hoped the new drugs won\u2019t need to be taken so frequently – Image credit: Science Photo Library<\/p>\n

Realising the potential of blocking Activin E, the team investigated further. Through tests on mice<\/a>, they managed to show that Activin E proteins are messengers that allow the liver to talk to the body\u2019s fat stores via fat cell receptors.<\/p>\n

\u201cThey act on the fat-storing cells to modulate how you store fat,\u201d Sleeman explains. \u201cIf you eat too much food, you have to have somewhere to store it, so you put it in your fat. [Activin E] is one of the secreted factors that\u2019s able to regulate where you store your energy.\u201d<\/p>\n

Targeting Activin E, then, could prevent fat hoarding, allowing more of it to be converted to energy so that \u2013 hopefully \u2013 the body resorts less to breaking down muscle.<\/p>\n

However, while most of Regeneron\u2019s therapies use antibodies to block proteins, it hasn\u2019t yet announced human trials of any Activin E blockers.<\/p>\n

Sleeman says his team wants to fully understand what the messenger and its receptors do first.<\/p>\n

Gene slicing<\/p>\n

Other companies are trying a different approach to stop the messages from getting through to fat tissues.<\/p>\n

US companies Arrowhead Pharmaceuticals and Alnylam both make gene-silencing therapies that take out specific proteins at their source.<\/p>\n

The medicines target the DNA<\/a> sequences coding for the proteins using short stretches of RNA<\/a> \u2013 known as siRNAs (small interfering RNAs).<\/p>\n

\"AnAn illustration of an RNA molecule. Pharmaceutical companies are using gene silencing, a process that involves RNA interference, to target visceral fat – Image credit: Science Photo Library<\/p>\n

It\u2019s like \u201cturning off the faucet\u201d for these signalling proteins, explains Dr James Hamilton<\/a>, Arrowhead\u2019s chief medical officer and head of research and development.<\/p>\n

The California-based company has two drugs targeting the Activin E pathway in human trials \u2013 one (ARO-INHBE) targeting the Activin E gene itself<\/a> and the other (ARO-ALK7) targeting the gene for its receptor<\/a>, ALK7, on fat cells.<\/p>\n

Although these are early trials, looking at effects in less than 100 people each, so far the results look promising.<\/p>\n

\u201cWe\u2019ve seen in some of our early clinical trials that targeting the [Activin E] pathway might have benefits specific to visceral fat, which is the most problematic fat \u2013 it\u2019s the fat that accumulates around organs, which is inflammatory and can predispose people to things like type 2 diabetes,\u201d Hamilton says.<\/p>\n

Preliminary data shows patients drop 14 per cent of their visceral (\u2018belly\u2019) fat within eight weeks on a single dose of ARO-ALK7.<\/p>\n

What\u2019s more, early data from the ARO-INHBE trial suggests the drug could actually prevent muscle loss altogether.<\/p>\n

An advantage of this gene-silencing approach compared to antibody therapies is that the effects could last several months, Hamilton says.<\/p>\n

And compared to the current generation of GLP-1s, most of which are injected weekly, that\u2019s a big benefit.<\/p>\n

There\u2019s a caveat, though, as Dalamaga points out. \u201cThey may require less frequent dosing [but]\u2026 they\u2019re not quickly reversible if an unexpected problem appears.\u201d<\/p>\n

In the past, she adds, there have been concerns about the effects of gene-silencing drugs on the liver, for example, or how they might inadvertently switch off non-target genes that have similar DNA sequences.<\/p>\n

While modern drug designs have improved, extended trials will be needed to show that Activin E can be safely switched off for longer periods.<\/p>\n

Read more:<\/p>\n

Body comms<\/p>\n

Activin E isn\u2019t the only activin, however. There\u2019s a handful of others, some of which also talk to fat cells, as well as an array of receptors that bind to varying combinations of them.<\/p>\n

Their roles extend beyond metabolism, but if drug manufacturers can unravel the activins\u2019 complex communications to learn how they target fat loss and muscle preservation, they\u2019ll be on to a winner.<\/p>\n

Regeneron has been working on doing this for decades. Alongside its research on Activin E, the company is already in clinical trials with garetosmab<\/a>, an antibody that blocks Activin A \u2013 an activin with a role in fat cell development.<\/p>\n

In 2025, Regeneron also published results<\/a> of a trial in postmenopausal women, where researchers paired garetosmab with another antibody (trevogrumab) that blocks myostatin, a key protein driving muscle wasting.<\/p>\n

Together, the two drugs increased women\u2019s thigh muscle volume<\/a> while decreasing fat mass.<\/p>\n

\u201cThat was a very pivotal early study,\u201d Sleeman says, adding that sarcopenia \u2013 age-related muscle loss \u2013 is important in both men and women.<\/p>\n

Components of activin receptors are also the target of bimagrumab, an antibody originally developed by Mounjaro\u2019s US manufacturer Eli Lilly to treat muscle-wasting disorders, but now in mid-stage clinical trials<\/a> to test its safety and efficacy as a weight-loss drug.<\/p>\n

Results published in 2026<\/a> suggest the drug strips fat almost as fast as a GLP-1 (semaglutide).<\/p>\n

But where it may excel is in preserving muscle \u2013 those on bimagrumab lost barely 1 per cent of their lean mass compared to 5\u20137 per cent in those who took GLP-1.<\/p>\n

\"ImageA key focus of some drugs currently being trialled is the process of \u2018browning\u2019 unhealthy white adipose tissue, or white fat, to improve metabolism – Image credit: Science Photo Library<\/p>\n

Interestingly, though, the best results were seen in those who took both drugs (bimagrumab and semaglutide). They lost more fat than with either drug alone \u2013 over a third of their belly fat \u2013 while still only sacrificing 1\u20132 per cent of their lean mass.<\/p>\n

According to Dalamaga, who covered bimagrumab in a recent review<\/a>, multiple new trials are now recruiting people to test the drug in combination with tirzepatide (Mounjaro). But there may still be a call for taking the drug on its own.<\/p>\n

\u201cFor someone who doesn\u2019t tolerate GLP-1 drugs, or an older person where preserving muscle is a major priority, a metabolism-focused drug on its own could make sense, even if the number on the scales doesn\u2019t drop as dramatically,\u201d she says.<\/p>\n

If there\u2019s a concern, it\u2019s that bimagrumab blocks components of receptors involved in transmitting messages for multiple activin pathways. And activins don\u2019t just talk to fat cells.<\/p>\n

So, while side effects in early trials have been limited mainly to muscle spasms, acne and diarrhoea, Dalamaga suggests we need to watch out for more dangerous ones.<\/p>\n

\u201cSo far, the available trial data has been generally reassuring, but we\u2019re interfering in a system whose full range of actions we don\u2019t completely understand,\u201d she warns.<\/p>\n

Activins are known to be involved in important processes like reproduction, immunity, wound healing and more.<\/p>\n

The same concerns could be extended to metabolic \u2018master switches\u2019 that some companies are trying to flip to reset metabolism in an even broader way.<\/p>\n

Biotech company Resalis Therapeutics<\/a>, based in Turin, Italy, for instance, is testing RES-010, a drug that targets a well-studied genetic switch known as miR-22.<\/p>\n

A metabolic regulator<\/a>, miR-22 is a short piece of natural RNA that can control various metabolic pathways \u2013 some of which cross over with activin pathways.<\/p>\n

From a drug manufacturer\u2019s perspective, perhaps its most interesting quality is that it suppresses messages promoting conversion of fat-storing tissue to fat-burning tissue.<\/p>\n

Thus, switching it off should be metabolically beneficial.<\/p>\n

\u201c[RES-010] changes the way in which the body uses fats, boosts the production and activity of mitochondria \u2013 the \u2018batteries\u2019 that power cells \u2013 and helps convert white fat (which stores energy) into brown fat (which burns it),\u201d Dr Riccardo Panella<\/a>, chief scientific officer at Resalis, told a meeting of scientific experts discussing diabetes in Vienna, Austria last September.<\/p>\n

\"CGScientists are testing a drug that switches off a metabolic regulator in the body so fat is broken down rather than stored – Image credit: Getty Images<\/p>\n

Thus far, however, the best data came from a recently-ended Phase 1 trial (which Resalis would not comment on) and studies in non-human primates.<\/p>\n

In the primate studies<\/a>, animals lost close to 15 per cent of their body fat on both RES-010 and semaglutide over 10 weeks, but just 1 per cent of their lean mass with RES-010 versus 8 per cent with semaglutide.<\/p>\n

Resalis claims that the fundamental action of its drug should reduce the likelihood of weight regain.<\/p>\n

But while animals did have less rebound compared to the GLP-1, the follow-up period appears to have been just four weeks.<\/p>\n

A combined approach<\/p>\n

This brings us back to the first problem with GLP-1s and the question of whether any of these new metabolism-altering approaches \u2013 either alone or paired with a GLP-1 appetite modifier \u2013 can delay the inevitable regain when patients stop the drugs.<\/p>\n

\u201cA good balance between reducing food intake and increasing energy expenditure would be a very sound approach, and I think it\u2019d be more prolonged,\u201d says Sleeman, hinting that combined appetite-and metabolic-changing approaches look promising.<\/p>\n

Meanwhile, Dalamaga says it\u2019s too early to presume that stopping any obesity drug would lead to lasting results without ongoing treatment.<\/p>\n

And Hamilton expresses only cautious optimism about slower weight regain based on \u201cinteresting animal studies\u201d at other companies.<\/p>\n

Nevertheless, we may soon start to learn more about the power of metabolic modification as drug makers test a new generation of GLP-1s mixed with other molecules.<\/p>\n

Eli Lilly\u2019s experimental retatrutide (\u2018Triple G\u2019), for example, combines GLP-1 with two other hormones \u2013 GIP and glucagon, which is partly intended to help people burn more fat.<\/p>\n

Very recent trials<\/a> also suggest that even approved, dual-action drugs like Mounjaro (GLP-1 plus GIP) drive \u2018browning\u2019 of unhealthy white fat to improve metabolism \u2013 although how they do this is currently unclear.<\/p>\n

Whether this refocusing of the weight-loss market towards healthier metabolism is ultimately of benefit remains to be seen.<\/p>\n

In a sense, worrying less about what we put in our mouths \u2013 because we\u2019ve changed what our bodies do with it \u2013 could mean people pay less attention to healthy eating.<\/p>\n

Dalamaga, however, is less cynical. \u201cI wouldn\u2019t frame it [like that],\u201d she says. \u201cThe real goal is to make obesity treatment healthier and more biologically complete, while still recognising that nutrition, physical activity and resistance exercise remain important for long-term health.\u201d<\/p>\n

The broader point, she says, is that the field is moving away from judging success purely by total weight loss and towards an ideal of better body composition.<\/p>\n

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