The analyses evaluated three GLP-1 receptor agonists used for weight management and found that each one produced clinically important weight loss when compared with placebo. Even so, there is still limited or uncertain evidence about their long-term safety, possible side effects, and how financial ties might influence study results.

Glucagon-like peptide-1 (GLP-1) receptor agonists were first introduced in the mid-2000s to help people with type 2 diabetes. In that setting, particularly among those with underlying heart or kidney disease, the drugs helped improve blood sugar levels, lowered the risk of related complications, aided weight reduction, and reduced the likelihood of early death.

More recently, researchers have been testing GLP-1 receptor agonists in people with obesity. These medications work by imitating a natural hormone that slows digestion and helps individuals feel full for longer. In the United Kingdom, they are approved for weight management when combined with a reduced calorie diet and physical activity for people with obesity or for those who are overweight with related health issues.

GLP-1 drugs show promise for weight management

Across the reviewed studies, tirzepatide, semaglutide, and liraglutide consistently led to significant weight loss over one to two years compared with placebo, and the benefits appeared to continue during ongoing treatment.

• Tirzepatide (administered once weekly) produced about a 16% reduction in body weight after 12 to 18 months. Results from 8 randomized controlled trials (6 361 participants) indicated that these effects might last up to 3.5 years, although long-term safety data remain limited.
• Semaglutide (also injected weekly) was associated with an average weight loss of around 11% after 24 to 68 weeks, with evidence suggesting the effect can persist for up to two years, based on 18 randomized controlled trials (27 949 participants). More people achieved at least a 5% weight reduction, but the drug caused higher rates of mild-to-moderate gastrointestinal issues.
• Liraglutide (a daily injection) resulted in an average 4-5% weight loss in 24 trials (9 937 participants), still outperforming placebo. Evidence on benefits beyond two years was more limited.

The reviews found little to no difference between the drugs and placebo when looking at major cardiovascular events, mortality, or quality of life. However, nausea and digestive discomfort appeared more often among people taking GLP-1 drugs, and some participants discontinued treatment because of these side effects.

"These drugs have the potential to bring about substantial weight loss, particularly in the first year," says Juan Franco, co-lead researcher from Heinrich Heine University Düsseldorf, Germany. "It's an exciting moment after decades of unsuccessful attempts to find effective treatments for people living with obesity."

Independent research and equitable access are key

Most of the studies included in the reviews were funded by the companies that manufacture the drugs and were shaped by those companies in terms of design, analysis, and reporting. This has raised questions about potential conflicts of interest and highlights the importance of independent research.

The authors also stressed that the use of these medications should be viewed in a broader health context, including issues such as access, affordability, and insurance coverage, so that existing health inequities are not made worse. Costs remain a major barrier, particularly for semaglutide and tirzepatide, while liraglutide has become more affordable since its patent expired. Semaglutide's patent is set to expire in 2026.

Most of the trials were conducted in middle- and high-income countries, with little or no representation from regions such as Africa, Central America, and Southeast Asia. Because body composition, eating patterns, and health behaviors differ around the world, the authors emphasized the need to understand how these drugs work in more diverse populations.

"We need more data on the long-term effects and other outcomes related to cardiovascular health, particularly in lower-risk individuals," says Eva Madrid, co-lead researcher from the Universidad de Valparaíso, Chile. "Weight regain after stopping treatment may affect the long-term sustainability of the observed benefits. More independent studies from a public health perspective are needed."

The reviews highlight the need for long-term, independent investigations to guide clinical and policy decisions and to better define the role of GLP-1 receptor agonists in lasting weight management.

Commissioned by the World Health Organization, the reviews will contribute to upcoming WHO guidelines on the use of GLP-1 receptor agonists for treating obesity.

The study -- published in Science Advances -- also offers a new angle on why modern humans ultimately surpassed Neanderthals. Lab-grown brain organoids with Neanderthal genetic variants reacted more strongly to lead than organoids with human genetics, hinting that Neanderthals may have been more vulnerable to lead's neurological effects.

Researchers from the Geoarchaeology and Archaeometry Research Group (GARG) at Southern Cross University (Australia), the Department of Environmental Medicine at the Icahn School of Medicine at Mount Sinai Hospital (New York, USA), and the School of Medicine at the University of California San Diego (UCSD, USA) combined fossil chemistry, brain organoid experiments, and evolutionary genetics to uncover how lead factored into hominid history.

Evidence of Ancient Lead Exposure in Fossil Teeth

For many years, lead toxicity was assumed to be closely tied to human industry, including smelting, mining, and the use of leaded petrol and paint. That view shifted when researchers analysed 51 fossil teeth from a range of hominids and great apes, including Australopithecus africanus, Paranthropus robustus, early Homo, Neanderthals, and Homo sapiens. The teeth showed clear chemical traces of intermittent lead exposure that stretch back nearly two million years.

High-precision laser-ablation geochemistry performed at Southern Cross University's GARG Facility (located in Lismore, NSW) and at Mount Sinai's Exposomics laboratories revealed distinct 'lead bands' in the enamel and dentine. These bands formed during childhood and indicate recurring periods of lead intake from environmental sources (such as polluted water, soil, or volcanic activity) or from lead stored in the body's bones and released during times of stress or illness.

"Our data show that lead exposure wasn't just a product of the Industrial Revolution -- it was part of our evolutionary landscape," said Professor Renaud Joannes-Boyau, Head of the GARG research group at Southern Cross University.

"This means that the brains of our ancestors developed under the influence of a potent toxic metal, which may have shaped their social behavior and cognitive abilities over millennia."

How Lead Interacted With Early Brain Development

To understand the functional impact of this exposure, the team studied human brain organoids, which serve as simplified, lab-grown models of early brain development. They tested how lead affected two versions of a key developmental gene known as NOVA1, which regulates gene expression under lead exposure during neurodevelopment. The modern human version of NOVA1 differs from the variant seen in Neanderthals and other extinct hominids, although the reason for this evolutionary change was previously unclear.

Organoids carrying the Neanderthal-like NOVA1 variant showed substantial disruptions in FOXP2-expressing neurons in the cortex and thalamus when exposed to lead. These brain regions are essential for language and speech development. Organoids with the modern human NOVA1 gene showed far less disruption.

"These results suggest that our NOVA1 variant may have offered protection against the harmful neurological effects of lead," said Professor Alysson Muotri, Professor of Pediatrics/Cellular & Molecular Medicine and Director of the UC San Diego Sanford Stem Cell Institute Integrated Space Stem Cell Orbital Research Center.

"It's an extraordinary example of how an environmental pressure, in this case, lead toxicity, could have driven genetic changes that improved survival and our ability to communicate using language, but which now also influence our vulnerability to modern lead exposure."

Genetic Insights Into the Rise of Modern Humans

Genetic and proteomic data from the study showed that lead exposure in organoids with archaic gene variants disrupted multiple pathways tied to neurodevelopment, communication, and social behavior. The FOXP2 disruptions are especially noteworthy because of FOXP2's well-established role in speech and language. These results suggest that long-term pressure from environmental toxins may have nudged cognitive and communicative traits along different evolutionary paths in modern humans and Neanderthals.

"This study shows how our environmental exposures shaped our evolution," said Professor Manish Arora, Professor and Vice Chairman of Environmental Medicine.

"From the perspective of inter-species competition, the observation that toxic exposures can offer an overall survival advantage offers a fresh paradigm for environmental medicine to examine the evolutionary roots of disorders linked to environmental exposures."

What Ancient Lead Exposure Means for Us Today

Although modern lead exposure is mostly linked to industrial activities, it continues to pose a serious health threat, especially for children. The new findings show that human susceptibility to lead may be deeply rooted in our evolutionary past and shaped by interactions between genes and environmental conditions.

"Our work not only rewrites the history of lead exposure," added Professor Joannes-Boyau, "it also reminds us that the interaction between our genes and the environment has been shaping our species for millions of years, and continues to do so."

The research drew on fossil teeth from Africa, Asia, Europe, and Oceania, using detailed geochemical mapping to trace childhood episodes of lead intake. In parallel, brain organoids containing either modern or archaic NOVA1 genes were used to study how lead affected brain development, with particular attention to FOXP2, a gene central to language. Genetic, transcriptomic, and proteomic analyses were combined to build a broad understanding of how lead may have influenced the evolution of hominid cognition and social behavior.