Recently, there has been a surge of interest in medications that claim to facilitate weight loss without the discomfort of hunger. These drugs, known as GLP-1 receptor agonists, are under scrutiny by the World Health Organization (WHO), which is evaluating their effectiveness and safety as potential solutions for obesity treatment.
Originally designed for managing type 2 diabetes, GLP-1 receptor agonists began clinical use in the mid-2000s. They have been shown to improve blood sugar control and reduce the risk of cardiovascular and kidney complications in diabetic patients, particularly those with existing heart or kidney issues. More recently, these medications have been tested in individuals with obesity. They work by mimicking a natural hormone that slows digestion and promotes a feeling of fullness.
To substantiate future guidelines regarding the use of these drugs for obesity management, the WHO commissioned three new Cochrane reviews. These reviews provide evidence that GLP-1 medications can lead to clinically significant weight loss compared to placebos. However, concerns arise from studies funded by the pharmaceutical industry, raising questions about the validity of the findings.
The reviews analyzed the effects of three weight loss medications: tirzepatide, semaglutide, and liraglutide. All three were found to induce significant weight loss after one to two years when compared with placebo treatments. Specifically, tirzepatide, administered weekly, resulted in a weight reduction of approximately 16% after 12 to 18 months. Evidence from eight randomized controlled trials involving over 6,300 participants indicated that these effects might persist for as long as 3.5 years, although long-term safety data are still scarce.
Semaglutide, also injected weekly, demonstrated an average weight loss of around 11% after a period of 24 to 68 weeks, with findings from 18 randomized controlled trials involving nearly 28,000 participants suggesting that results could be sustained for up to two years. This drug increased the likelihood of achieving at least a 5% reduction in body weight but was associated with higher rates of mild to moderate gastrointestinal side effects.
Liraglutide, administered daily, resulted in a more modest average weight loss of about 4-5%, according to 24 trials with nearly 9,940 participants. Nevertheless, it still increased the proportion of individuals experiencing significant weight loss compared to the placebo group. Evidence on long-term effects beyond two years was more limited.
Although there were minimal differences in major cardiovascular events, quality of life, or mortality rates between these medications and placebos, adverse events, particularly nausea and digestive symptoms, were more common among participants receiving GLP-1 treatments. Some patients discontinued their use due to these side effects.
Juan Franco, lead co-investigator from Heinrich Heine University in Düsseldorf, Germany, noted, “These medications have the potential for substantial weight loss, especially during the first year.” He highlighted the excitement surrounding this breakthrough after decades of unsuccessful attempts to find effective treatments for obesity.
It is noteworthy that most studies included in these reviews were funded by pharmaceutical companies, which were actively involved in the planning, execution, analysis, and reporting of results. This raises concerns about potential conflicts of interest and emphasizes the need for independent research.
The authors of the reviews also stressed that the broader use of these medications should consider social and commercial health determinants such as access, affordability, and insurance coverage to prevent exacerbating existing health disparities among people with obesity. The high costs associated with semaglutide and tirzepatide currently limit access, whereas the expired patent of liraglutide has allowed for the availability of more affordable generic versions. The patent for semaglutide is also set to expire in 2026.
Most studies in the reviews were conducted in middle- and high-income countries, with little to no representation from regions such as Africa, Central America, and Southeast Asia. Given the variations in body composition, diet, and health habits across populations, the authors emphasize the importance of assessing the performance of these medications in diverse global contexts.
Eva Madrid, co-investigator at University of Valparaíso in Chile, remarked, “We need more data on long-term effects and other cardiovascular health outcomes, especially in lower-risk individuals.” She expressed concern that weight regain after discontinuation of treatment could impact the long-term sustainability of observed benefits. There is a clear call for more independent studies from a public health perspective.
The reviews underline the necessity for independent and long-term research to support clinical decisions and public policy, ultimately clarifying the role of GLP-1 receptor agonists in long-term weight management. These findings, commissioned by the WHO, will form the basis for forthcoming guidelines regarding the use of GLP-1 receptor agonists in obesity treatment, which are anticipated to be released following a public consultation held in September.
