Large study points to benefits - and risks - of GLP-1 drugs
People who take weight-loss drugs based on GLP-1 receptor agonists seem to have reduced risk for a litany of diseases, including Alzheimer's, but an increase in some other conditions like kidney stones, low blood pressure, arthritis and joint pain, and pancreatitis.
Those are the findings of an observational study that claims to be the largest ever conducted on the drug class – based on 2.4 million people in the US Department of Veterans Affairs health record databases, including a cohort of 215,000 treated with GLP-1RAs – and has been published in the journal Nature Medicine.
It compared health outcomes among patients taking GLP-1RAs like Novo Nordisk's semaglutide and Eli Lilly's tirzepatide for diabetes and obesity to 'usual care' – in other words other standard drug classes used for diabetes, including sulfonylureas, DPP4 inhibitors and SGLT2 inhibitors.
Compared to usual care, GLP-1RA use was linked to a reduced risk of various neurocognitive disorders, substance use and psychotic disorders, seizures, coagulation disorders, cardiometabolic disorders, infectious illnesses, and several respiratory conditions.
It's a timely look at the drug glass, given that a recent study suggested that one in eight people in the US has taken or is currently using the drugs to treat diabetes and obesity, as well as to reduce the risk of cardiovascular disease, according to senior author Ziyad Al-Aly of John J Cochran Veterans Hospital in St Louis.
"Our approach has allowed us to build a comprehensive atlas mapping the associations of GLP-1RA spanning all organ systems," he said, noting that it is important to systematically examine their effects on all body systems […] to understand what they do."
"The study's results provide insights into some known and previously unrecognised benefits and risks of GLP-1RA that may be useful to inform clinical care and guide research agendas.
While observational studies are hard to interpret and generally don't influence clinical practice or public health policy – and this one was skewed towards a population of older, white males – the associations they reveal can be useful in guiding prospective studies to explore potential benefits or risks.
GLP-1-directed drugs have already shown promise in clinical trials involving people with sleep apnoea – Lilly's Zepbound (tirzepatide) was approved for that indication in the US last year – along with heart failure, kidney disease, and metabolic dysfunction-associated steatohepatitis (MASH), and Alzheimer's, amongst other indications.
Additional findings are likely to come from the plethora of large-scale, randomised clinical trials with GLP-1RA-based therapies for weight loss that in some cases include long-term follow-up.
Commenting on the study, Professor Sir Stephen O'Rahilly, who is director of the Wellcome-MRC Institute of Metabolic Science-Metabolic Research Laboratories at the University of Cambridge in the UK, said that it is encouraging that the already-demonstrated benefits of GLP-1RAs on heart disease, stroke, and other cardiovascular and kidney diseases are apparent in the new study.
"There is also a reassuring reduction in the incidence of several cancers, including pancreatic," he continued. "Importantly, as there has been discussion in the media about possible adverse effects of the drugs on mental health, the group taking the drug had a lower incidence of schizophrenia, alcohol and drug use disorders, and less suicidal ideation."
While the cause of the adverse effects needs exploration, Prof O'Rahilly suggested that low blood pressure and kidney stones could result from known gastrointestinal side effects of GLP-1RAs like diarrhoea could lead some people to become dehydrated, while joint pain could result from increased physical activity that is made possible when people lose substantial amounts of weight.
"On the other hand, the fact that receptors for GLP-1 are present on subsets of immune cells means that, until we have deeper knowledge, the effects of these drugs on inflammatory responses are somewhat unpredictable."
