SGLT2 Inhibitors May Offer Long-Term Knee Osteoarthritis Protection, Study Suggests
For years, GLP-1 agonists like semaglutide have been hailed as potential game-changers not just for diabetes management, but also for mitigating the risk of osteoarthritis. But a large, five-year emulation study presented at the 2025 American College of Rheumatology Meeting throws a surprising wrench into that narrative. The research suggests that, surprisingly, long-term use of GLP-1 agonists may actually increase the risk of knee replacement surgery compared to a different class of diabetes drugs, SGLT2 inhibitors. This finding underscores the critical importance of considering long-term adherence and individual drug characteristics when evaluating the benefits of these medications.
The Counterintuitive Findings: GLP-1s and Knee Replacement Risk
The study, analyzing data from over 323,000 individuals, revealed a per-protocol analysis showing an 18% higher risk of total knee replacement surgery in those initiating GLP-1 agonists versus SGLT2 inhibitors (RR 1.18; +8.5 cases per 1,000 initiators). Incident osteoarthritis also showed a 16% increased risk (RR 1.16; +23.3 cases per 1,000) with GLP-1 use. This is a significant finding, particularly given the rising prevalence of both type 2 diabetes and osteoarthritis, and the increasing use of these medications.
However, the researchers were quick to point out the complexities of interpreting these results. Intention-to-treat analyses, which account for patients who discontinue or switch medications, showed no significant difference between the two drug classes. This highlights a crucial point: real-world adherence significantly impacts the observed effects of these drugs.
Semaglutide: A Potential Exception to the Rule?
Digging deeper, the study revealed a fascinating nuance. When researchers separated out semaglutide – a particularly potent GLP-1 agonist – from other GLP-1s, the increased risk of knee replacement disappeared. In fact, there was no significant difference observed between semaglutide users and those on SGLT2 inhibitors regarding either knee prosthesis or osteoarthritis incidence. This suggests that the specific GLP-1 agonist used may play a critical role in its impact on joint health.
Conversely, non-semaglutide GLP-1 agonists did show a consistent advantage in favor of SGLT2 inhibitors. This raises questions about the mechanisms of action of different GLP-1 agonists and their varying effects on musculoskeletal health.
The Role of Weight Loss and Metabolic Pathways
The study acknowledged the challenge of accurately analyzing the impact of patient weight. Weight loss is a known benefit of GLP-1 agonists, and it’s a complex factor in osteoarthritis development. While weight loss generally reduces stress on joints, the rapid weight loss induced by some GLP-1s could potentially have unintended consequences. SGLT2 inhibitors, while also promoting weight loss, tend to do so at a slower pace.
SGLT2 inhibitors have demonstrated pleiotropic effects – meaning they impact multiple biological pathways – beyond glucose control. These effects include improvements in inflammation and cardiovascular health, which may contribute to their potential protective effect on joints.
Future Directions: Pragmatic Trials and Intra-Articular Therapies
The authors of the study emphasize the need for more robust research to clarify these findings. They advocate for pragmatic, randomized controlled trials comparing SGLT2 inhibitors and GLP-1 agonists (stratified by semaglutide use, initial weight, weight loss rate, and osteoarthritis phenotypes). These trials should prioritize standardized collection of patient-centered data, including pain levels, functional capacity, and time to surgery.
Interestingly, research is also underway on intra-articular GLP-1 agonists – injections directly into the knee joint. This approach aims to deliver higher doses of the medication to the affected area, potentially maximizing therapeutic benefits while minimizing systemic side effects.
The Rise of Personalized Medicine in Osteoarthritis Management
This research underscores a growing trend in medicine: the move towards personalized treatment approaches. The “one-size-fits-all” model is becoming increasingly obsolete. Factors like individual weight, metabolic profile, and specific osteoarthritis characteristics will likely play a greater role in determining the optimal treatment strategy.
See our guide on personalized osteoarthritis treatment options for more information.
Frequently Asked Questions
What are GLP-1 agonists and SGLT2 inhibitors?
GLP-1 agonists and SGLT2 inhibitors are both classes of medications primarily used to treat type 2 diabetes. They work through different mechanisms to lower blood sugar levels, and both have shown potential benefits beyond glucose control.
Does this mean I should stop taking my GLP-1 agonist?
No, absolutely not. This study highlights the need for further research and doesn’t warrant immediate changes to your medication regimen. Discuss any concerns with your healthcare provider.
What is the role of semaglutide in this research?
Semaglutide, a specific GLP-1 agonist, did not show the same increased risk of knee replacement surgery as other GLP-1s in this study. This suggests that different GLP-1 agonists may have varying effects on joint health.
What are the next steps in researching this connection?
Researchers are calling for larger, more comprehensive clinical trials to confirm these findings and to better understand the underlying mechanisms driving the observed effects. Trials focusing on intra-articular GLP-1 agonists are also underway.
The evolving understanding of the interplay between diabetes medications and musculoskeletal health is a critical area of research. As we learn more, we can refine treatment strategies to optimize patient outcomes and minimize the risk of long-term complications. What are your thoughts on the potential for SGLT2 inhibitors to become a first-line option for osteoarthritis prevention in diabetic patients? Share your perspective in the comments below!
