The twincretins are here, the tricretins are coming…

Semaglutide has taken the world by storm, almost single-handedly changing the economy of Denmark, where its manufacturer Novo Nordisk hails from, and leaving many diabetes patients in a lurch when social media users spruiked the weight loss benefits of off-label use of Ozempic, leading to continuing worldwide shortages.

In Australia, Ozempic has only been approved and funded for lowering blood glucose levels in people with type 2 diabetes, and Wegovy, the higher dose version of semaglutide, which has been approved specifically for weight loss, is still not available here — but are these GLP-1 receptor agonists (GLP-1 RAs) already about to be superseded?

What’s coming around the corner?

Tirzepatide, sold as Mounjaro by Eli Lilly, is already used for type 2 diabetes and is expected to receive approval in the US in the next months to treat obesity.

Tirzepatide works by binding to GIP and GLP-1 receptors. This dual agonist behaviour, which gives it the name twincretin, has been shown to reduce hyperglycemia and body weight more effectively than a selective GLP-1 RA in type 2 diabetes patients.

Meanwhile Eli Lilly has a triple hormone receptor agonist called retatrutide, in the last stage of clinical trials.

“We haven’t had drugs as effective as this before,” says John Dixon, Adjunct Professor at the Iverson Health Innovation Research Institute, Swinburne University of Technology, Melbourne. “A whole string of them now looks very promising, but we can only really assess the ones that have been through and been approved.”

Quick refresher on GLP-1 RAs

Semaglutide works by mimicking glucagon-like peptide 1, or GLP-1. The hormone is produced in the gut in response to food and instructs the pancreas to make insulin. GLP-1 receptors also exist within the hypothalamus, in a region involved in appetite regulation and reward. Activating these receptors with GLP-1 copycats, which last longer in the body than the natural hormone, induces feelings of fullness, slows stomach emptying, and decreases the reward associated with eating.

In a clinical trial, participants who took once-weekly semaglutide for over a year lost, on average, 16% of their body weight, about twice as much as people treated with once-daily liraglutide, an older GLP-1 RA.

Another study that involved adults with obesity and type 2 diabetes found that those treated with semaglutide for over a year could, on average, lost 10% of their weight compared with a 3% loss in people who had a placebo.

This is significant since losing greater than 10% of body weight can lead to diabetes remission — but for those who want or need to lose more weight than that, semaglutide and other GLP-1 RAs that only target one receptor don’t reach the levels of bariatric surgery, where people commonly achieve 30% weight loss.

Twincretins and beyond

Over the past decade, researchers have been developing drugs that mimic GLP-1 and another hormone, glucose-dependent insulinotropic polypeptide (GIP), to see whether activating both receptors leads to more weight loss.

One such dual agonist drug is Eli Lilly’s Mounjaro (tirzepatide). In a phase 3 trial, participants who took the highest dose for almost 1.5 years lost an average of 21% of their body weight, with 85% losing at least 5%.

Other drugs in development inhibit GIP receptors. AMG-133, a candidate developed by Amgen, turns off GIP receptors while activating GLP-1 receptors. In an early-stage clinical trial, the highest dose resulted in a 15% body weight loss after three months.

To create an even more potent agent, scientists combined GLP-1 and GIP agonists with yet another gut hormone: glucagon. Activating glucagon receptors raises blood sugar by signalling the liver to produce glucose. However, it also initiates a process that breaks down fat in the liver and increases energy consumption, possibly by activating the sympathetic nervous system.

In a phase 2 clinical trial, participants receiving the triple agonist retatrutide once weekly for almost a year lost, on average, 24% of their body weight. “The trajectory of the weight loss curve is going further down,” says Professor Matthias Tschöp, physician and scientist CEO and scientific director of Helmholtz Zentrum München, Germany. “So we can speculate that we are going to hit 28 – 30% weight loss, which puts these triple combinations where bariatric surgery is.”

Beyond losing weight

The benefits of these potent obesity treatments extend beyond weight control. In 2011, it was estimated that about 53% of the Australian diabetes burden was due to overweight and obesity.

In those who already have diabetes, these medications reduce blood sugar levels. In more than half of the patients treated with tirzepatide, for example, HbA1c levels were normalised after 40 weeks.

Achieving and maintaining a healthy body weight is a substantial leap in reducing cardiovascular risk. It enhances metabolism and blood lipid profiles and diminishes liver fat.

Recent evidence suggests that semaglutide may also directly influence the cardiovascular system. This effect could be mediated through brain and autonomic nervous system receptors, impacting cardiovascular regulation, or via receptors at the heart and vasculature, with implications for cardiovascular function and hypertension, explains Professor Dixon.

In a large study, that has not yet been peer-reviewed, patients who were overweight or obese and had cardiovascular disease but no history of diabetes saw their likelihood of serious cardiac events such as heart attacks, strokes, and cardiovascular deaths cut by 20%.

Although research on long-term cardiovascular effects is ongoing, emerging data indicate that gut hormones positively impact cardiovascular risk but less so in people with type 2 diabetes. “We don’t have enough data yet. However, there seems to be a pattern that activation of GLP-1 receptors has fewer [cardiovascular] benefits in patients with diabetes. The hope is that double and triple agonists can overcome that,” says Professor Tschöp.

The downsides

Drugs that activate GLP-1, like Ozempic and Wegovy, can cause gastrointestinal adverse events like nausea and vomiting. In the type 2 diabetes trial testing 0.5 mg and 1.0 mg of semaglutide for 104 weeks, 11.5% and 14.5% of participants, respectively, discontinued treatment prematurely because of nausea, vomiting or diarrhea, versus 5.7% and 7.6% in the placebo group.

Activating GIP receptors, as well as GLP-1, as Mounjaro does, seems to mitigate some of the unpleasant side effects caused by the activation of GLP-1 receptors.

However, in the phase 3 study testing Mounjaro as an obesity treatment, many participants still reported mild or moderate gastrointestinal problems during dose escalation. Adverse events led 4.3%, 7.1% and 6.2% of participants receiving 5 mg, 10 mg, and 15 mg tirzepatide doses, respectively, to discontinue the treatment – and 2.6% of those who got placebo also discontinued due to adverse events.

A trial of Wegovy showed that 4.5% of participants discontinued due to gastrointestinal effects (compared with 0.8% of the placebo group).

Clinicians should warn patients of possible gastrointestinal adverse events, experts say. However, they can use techniques, such as increasing the dosage of the drugs slowly, to mitigate these effects.

Professor Dixon says the drugs that have been approved by the regulatory bodies are generally safe, considering they have been studied and used for some time to treat type 2 diabetes. “These drugs haven’t come out of nowhere. They have been tested thoroughly.”