'Trojan horse' weight loss drug outperforms Ozempic in mice

A revolutionary new approach to weight loss could rise above medications like Ozempic and Wegovy. By combining the appetite-suppressing hormone GLP-1 with special molecules that zero in on the brain's appetite control center, this "Trojan horse" therapy achieved remarkable weight loss in mice – up to twice as much as GLP-1 alone in some cases.

The drug co-developed by scientists at the University of Copenhagen and Novo Nordisk smuggles in molecules that directly regulate hunger alongside GLP-1. While currently approved GLP-1 medications just make people feel fuller, this two-pronged offensive strikes the appetite at its neurological roots.

"The effect of GLP-1 combined with these molecules is very strong. In some cases, the mice lose twice as much weight as mice treated with GLP-1 only," said lead researcher Christoffer Clemmensen, an associate professor.

On Ozempic, Wegovy and comparable GLP-1 agonists, people typically shed 15-20% of their weight, though around a third lose just 10% according to Columbia University's Department of Surgery. Clemmensen believes his combination punch could help patients achieve similar or superior results at lower, less side effect-prone doses – and may succeed where current options have failed.

In their study, mice experienced GLP-1-induced nausea akin to human users. However, Clemmensen is hopeful that "since the drug works so well, we can reduce the dosage enough to avoid many side effects." Common adverse effects include diarrhea, vomiting, constipation and stomach pain.

The drug must clear three phases of clinical trials over an estimated eight-year timeline. But the study's tantalizing findings, published recently in Nature, are sending shockwaves through a field starved for more potent obesity and metabolic disease therapies.

Over 40% of U.S. adults are obese, raising their risks of heart disease, stroke, type 2 diabetes, certain cancers and more. Modest weight loss can significantly boost health, yet lasting lifestyle changes prove immensely difficult for most. Medications provide a much-needed boost when diet and exercise fall short.

The body releases GLP-1 after eating to lessen cravings by activating fullness receptors in the brain and gut. Ozempic, Wegovy and peers in the GLP-1 agonist class mimic this natural satiety signal.

But the dearth of treatments delivering over 10-15% weight loss underscores the challenge of developing safe, effective obesity drugs. Many older medications were pulled due to serious side effects like heart valve damage.

Across multiple obese mouse models, combining GLP-1 with hypothalamus-modulating agents consistently amplified benefits. "We witnessed a remarkable 20% weight loss from baseline, considered the reversal threshold in rodents," Clemmensen said.

Beyond curbing appetite and weight regain post-dieting, the combo also boosted insulin sensitivity to combat diabetes, revved up resting metabolism, and optimized fat burning.

While a long road remains, Clemmensen foresees this holistic remodeling of neural appetite pathways as a launchpad for future weight loss breakthroughs. "By impacting brain plasticity, we may unlock even greater progress than today's treatments allow."