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GLP-1 receptor agonist drugs are effective but come with complex concerns

Although glucagon-like peptide-1 receptor agonists (GLP-1RAs) are highly effective for weight management and Type 2 diabetes treatment, there are complex considerations such as dosages, costs, side effects and comparisons between specific drugs researchers from the University of Chicago Medical Center suggest.

Network of available comparisons between GLP-1RAs and placebo for weight loss. The size of the nodes is proportional to the number of trial participants, and the thickness of the line connecting the nodes is proportional to the randomized number of trial participants directly comparing the two treatments. Numbers represent the number of trials contributing to each treatment comparison (Credit: BMJ (2024). DOI: 10.1136/bmj-2023-076410).

"The current fervour for GLP-1RAs in the capital markets as well as in the general public, especially in terms of weight reduction, is probably going to result in overuse," said Dr Chun-Su Yuan, the Cyrus Tang Professor of Anesthesia and Critical Care at the University of Chicago. "This should raise a red flag. Some other treatments for Type 2 diabetes can actually cause weight gain, whereas GLP-1RA drugs effectively control blood glucose levels while also reducing body weight.”

Yuan and a group of other researchers recently published a paper, ‘Comparative effectiveness of GLP-1 receptor agonists on glycaemic control, body weight, and lipid profile for type 2 diabetes: systematic review and network meta-analysis’, in the BMJ comparing the effectiveness of different GLP-1RAs. Different drugs performed better in different areas, but all 15 GLP-1RAs they analysed were very successful in lowering blood glucose and achieving weight loss. They also identified some secondary benefits, such as lowering cholesterol.

Similarly, Dr Eric Polley, a UChicago data science and public health expert, recently led a study, ‘Effectiveness of glucose-lowering medications on cardiovascular outcomes in patients with type 2 diabetes at moderate cardiovascular risk’, published in Nature Cardiovascular Research that used statistical modelling to simulate a clinical trial comparing the effects of four different classes of diabetes medication in patients with moderate cardiovascular risk. GLP-1RA drugs came out on top, not only controlling blood glucose and weight but also reducing the risk of major heart-related events and the risk of death overall.

However, GLP-1RAs are not universally effective for all patients, and Yuan said that even after deciding to prescribe this drug class, physicians should consider multiple factors when selecting a specific drug and dosage. For example, co-morbid conditions like hyperlipidaemia could tip the scale and make one drug more suitable for a specific patient.

Polley added that even patients with similar clinical profiles might prioritise different aspects of their health or quality of life.

"If cardiovascular health is what you think is important for deciding between these drug classes, I think our most recent study provides some strong evidence,” he explained. “But if there are other outcomes that your patient is concerned about, then you have to consider the effect size for those other outcomes.”

He and other experts are working on subsequent research examining the effects of different diabetes treatments on other health outcomes and concerns, including a patient's risk of cancer, blindness or amputation.

Another key consideration is side effects, which can vary significantly from patient to patient. While Yuan's recent study confirmed the efficacy of GLP-1RAs, the researchers also found that some patients did experience adverse side effects, especially related to gastrointestinal issues like nausea and vomiting. They highlighted the need to consider potential trade-offs between efficacy and side effects, finding that higher doses can have stronger efficacy but also induce more severe side effects.

"It's also important to note that the long-term side effects of these drugs are not yet well-studied," added Yuan. "If large swathes of the general public start taking them off-label for weight loss and then we find out years later that there are bad side effects, it could be a real issue."

Yet another dimension affecting the use of GLP-1RAs is cost. The drugs are expensive, and experts say the recent spike in popularity has already led to shortages and increased hesitancy among insurance providers to cover these drugs.

In pursuit of more equitable and cost-effective approaches to leveraging GLP-1RAs, Dr David Kim, a UChicago health economist and lead author of a study, ‘Balancing innovation and affordability in anti-obesity medications: the role of an alternative weight-maintenance program’, published in Health Affairs Scholar and a group of other researchers analysed the potential impact of alternative weight loss programmes.

"We know these drugs represent a massive breakthrough in our long fight against obesity-related clinical conditions, but their high cost has been the subject of substantial debate," said Kim. "It presents a key barrier to equitable access to this great innovation."

Specifically, they proposed an approach in which GLP-1RAs could be prescribed for an initial period of weight loss before patients transitioned to cheaper alternative interventions for weight maintenance such as lower-cost medications, behavioural health programs and support from nutritionists.

"We wanted to challenge the assumption that once you're on a GLP-1RA drug, you have to keep taking it forever," added Kim. "That's where some of the affordability concerns are coming from: large populations are potentially eligible to take these drugs, and we can't pay for a lifetime supply for everyone."

The researchers' model suggested that even though the alternative weight-maintenance programs might be slightly less effective than long-term, full-dosage GLP-1RA use, the clinical benefits would only decrease slightly, while lifetime health care spending would decrease substantially.

"We argue that this alternative framework is a viable solution that provides greater flexibility for managing a limited drug supply and giving health care payers financial headroom to support more patients accessing effective weight management treatment," Kim said.


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