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In just two decades, glucagon-like peptide-1 receptor agonists (GLP-1RAs) have evolved from a treatment for type 2 diabetes to one of the most widely prescribed medications for weight loss. The approval of Novo Nordisk’s semaglutide (Wegovy) for chronic weight management in 2021 marked a key milestone in the journey of these drugs, and their growing popularity has sparked a surge in sales. However, while trials for more advanced drugs, including dual and triple receptor agonists, continue, many critical questions about GLP-1RAs remain unanswered.
Experts are now seeking to understand the full extent of their effects, particularly as these drugs move beyond their original role in managing diabetes to potential treatments for a range of other health conditions. Despite their success, crucial information remains elusive on several fronts, including their impact on organ protection, addiction, neurodegeneration, and sex differences.
Organ Protection and Kidney Disease
GLP-1RAs were initially designed to help regulate blood sugar levels by enhancing insulin production in patients with type 2 diabetes. However, there is growing evidence that these drugs may offer broader benefits. Clinical pharmacologist Hiddo L. Heerspink from the University of Groningen believes GLP-1RAs may also protect organs in people without diabetes, but further studies are needed. Trials, such as the SELECT clinical trial, have shown that semaglutide can reduce cardiovascular risks in overweight individuals with heart disease. But researchers need more data to determine whether these benefits stem from the drugs’ direct effects on organs or from weight loss.
In addition, GLP-1RAs show promise in treating chronic kidney disease (CKD), which affects over 10% of the global population. The FLOW study found that semaglutide reduced mortality by 20% in people with type 2 diabetes and CKD. Yet, nephrologist Katherine Tuttle emphasizes the need for further research to understand how these drugs directly influence kidney health and whether their protective effects are independent of metabolic changes.
Length of Treatment and Broader Population Use
As GLP-1RAs continue to expand in use, many questions remain about how long patients should stay on these drugs. Robert Kushner, a researcher at Northwestern University, highlights the need for studies that explore the generalizability of GLP-1RA treatment in diverse populations. Clinical trials have largely focused on specific groups, leaving gaps in knowledge about the effectiveness and safety of these drugs in broader patient populations, including those with mental health issues or diverse racial and ethnic backgrounds.
Moreover, it is still unclear how long patients need to stay on GLP-1RAs, especially for weight loss. Kushner suggests randomized clinical trials to assess different treatment protocols, such as continued medication versus tapering or discontinuing treatment.
Addiction Treatment and Neurodegeneration
Researchers are also exploring the potential of GLP-1RAs to address addictive behaviors. Preliminary findings suggest these drugs may influence alcohol and tobacco use, with some studies showing reduced alcohol consumption and smoking in people treated with semaglutide or tirzepatide. However, experts like Helen Colhoun and Warren Bickel call for more clinical trials to fully understand how GLP-1RAs affect addiction.
Another area of interest is the potential role of GLP-1RAs in slowing cognitive decline and preventing neurodegenerative diseases like Alzheimer’s. Studies have already shown that diabetes increases the risk of dementia, but GLP-1RAs may help mitigate that risk by improving metabolic health. Naveed Sattar from the University of Glasgow stresses the need for long-term studies to definitively establish whether GLP-1RAs can reduce the onset of neurodegenerative diseases.
Sex Differences and Accessibility
Early data suggest that GLP-1RAs may affect men and women differently. Women appear to experience more gastrointestinal side effects, which could prevent some from benefiting from these drugs. However, they also seem to lose more weight than men, raising questions about gender differences in response to GLP-1RAs. Susan Cheng, a researcher at Cedars-Sinai, urges further studies to understand how sex differences might influence the effectiveness and safety of these treatments.
One of the major concerns surrounding GLP-1RAs is their cost. Currently, these drugs are expensive, with monthly prices ranging from $936 to $1,349 in the United States. Johannes Mann from Friedrich Alexander University calls for efforts to develop cheaper, orally administered versions of GLP-1RAs that could be more accessible to a wider range of patients.
The Future of GLP-1RAs
As GLP-1RAs continue to gain traction as both weight-loss medications and treatments for a variety of other conditions, the questions surrounding their long-term effects and broader applicability remain critical. Researchers are working to answer these questions, but it may take another decade of studies to fully understand the potential of these drugs. The growing use of GLP-1RAs could revolutionize treatment for obesity, diabetes, and beyond, but only time will tell how these medications will shape the future of healthcare.
