News release

From: BMJ Group

GLP-1 agonists linked to significantly lower long term risk of knee replacement

Greatest effect seen with sustained use and newer agents semaglutide and tirzepatide

GLP-1 receptor agonist drugs, used for the treatment of diabetes, and more recently, weight loss, are associated with a significantly lower long term risk of knee replacement surgery as a result of osteoarthritis, finds an analysis of medical records data, published in the open access journal Regional Anesthesia & Pain Medicine.

The greatest effects were seen with sustained use and the newer agents semaglutide and tirzepatide, the analysis indicates.

More than 300 million people worldwide have osteoarthritis, for which there are currently no effective disease modifying drug treatments. And the progressive nature of the condition can ultimately require knee replacement surgery, although not everyone is eligible for this option, note the researchers.

The prevalence of the condition is likely to rise in tandem with increasing rates of obesity and ageing populations, they add.

While the use of GLP-1 receptor agonists has been associated with reduced knee pain caused by osteoarthritis, emerging evidence suggests that they may have anti-

Inflammatory effects and may help protect cartilage from further damage, raising the prospect of their use in slowing osteoarthritis progression, explain the researchers.

To explore this further, they drew on anonymised data from the TriNetX Global Research Network to identify adults with knee osteoarthritis diagnosed between January 1 2010 and December 31 2024.

Patients were stratified into 4 categories: by treatment duration (1 or 3 years): and type of GLP-1 receptor agonist (any or the new generation agents semaglutide or tirzepatide).

Patients in each of these categories were then compared with patients with osteoarthritis who hadn’t been given these drugs, but with similar background characteristics, including age, sex, race, musculoskeletal diagnoses, obesity related conditions, markers of healthcare access, and weight (BMI), using propensity score methods.

Propensity scoring reduces the likelihood that baseline differences between groups explain the observed associations.

The need for total knee replacement surgery was assessed at 1, 3, 5, and 8 years after diagnosis.

Some 28,599 patients had been treated with new generation GLP-1 receptor agonists for 1 year, while 13,351 had been treated with these agents for 3 years; 42,062 had been treated with any of this class of drugs for 1 year while 30,981 had been treated with them for 3.

Analysis of the data showed that treatment with these drugs was associated with significantly fewer cases of knee replacement surgery at any time point, irrespective of treatment duration or intervals between the assessments.

For example, 1 year of treatment with any GLP-1 receptor agonist was associated with a 1.4 percentage point lower cumulative risk of knee replacement surgery at the 3 year assessment, with risk reductions increasing to nearly 3 percentage points at the 8 year assessment.

But the greatest reduction in risk was consistently seen with newer generation agents and longer treatment: at the 8 year assessment, 3 years of treatment with semaglutide or tirzepatide was associated with a nearly 5 percentage point lower cumulative risk.

“Our findings align with evidence that GLP-1 [receptor agonists] may influence knee [osteoarthritis] through complementary anti-inflammatory and analgesic mechanisms,”write the researchers.

They highlight various limitations to their findings and caution that unmeasured and potentially influential factors, such as frailty, physical activity, functional capacity, or osteoarthritis severity weren’t accounted for. And the data relied on prescription data, without confirmation that the drugs had actually been taken.

“Accordingly, these findings should be interpreted as observational associations consistent with potential disease modifying effects rather than evidence of causality,” they point out.

Nevertheless, the findings suggest that these drugs may prove a clinically meaningful complementary approach for the non-surgical treatment of knee osteoarthritis in eligible patients living with obesity or metabolic disease, they say.

“These sustained and duration dependent associations, supported by preclinical evidence of joint tissue modulation and clinical evidence of analgesic benefits, are consistent with the possibility of effects beyond symptomatic relief or weight loss alone,” they write.

“If confirmed in prospective trials, these associations could shift treatment paradigms

toward integrating metabolic health as a core component of joint preservation and inform guidelines on GLP-1 [receptor agonist] use in patients at risk of surgical progression,” they conclude.

By way of an example, they highlight that a 1 year absolute risk reduction of 1.44% observed after 3 years of treatment with a new generation GLP-1 receptor agonist translates into around 14,400 fewer total knee replacements every year in the US alone, with corresponding reductions in healthcare expenditures and surgical complications.