Osteoarthritis, Obesity and GLP-1s Save

We all know that osteoarthritis is the most common form of arthritis in the world and that obesity — which we're talking about here with the RheumNow obesity campaign — is its most modifiable risk factor. I'm Tom Appleton, rheumatologist and head of the division of rheumatology in London, Canada, University of Western Ontario.

What I really want to focus on today is the role that GLP-1 receptor agonists might be playing in our management of osteoarthritis in particular. So why does this matter? Osteoarthritis is a huge problem. It's probably the biggest unmet need in all of rheumatology, certainly the arthritis field overall. And our guidelines have mostly focused on things like pain management with analgesics, NSAIDs, intraarticular injections. Very important role to play with rehab and physical therapy. But, you know, we've really had osteoarthritis playing a minor role in our clinics in particular because there's no medicine, at least to date, that we've been able to prescribe that can really change the outcomes for people with osteoarthritis in a big way. So, we've been left with joint replacement surgery. Most of the time that only helps about up to 30% of the patient population. So, there's a huge unmet need.

Obesity is a very well-established and causal risk factor for osteoarthritis. Work that we've done, others have done, has clearly showed that if you have early stage osteoarthritis, you're more likely to progress to late stage disease or arthroplasty if you have obesity and or metabolic syndrome. And I really want to focus on reframing obesity from just a weight problem to a systemic metabolic problem, a cardiometabolic disease that has a major impact on outcomes in osteoarthritis.

So this sets up essentially a two-mechanism hypothesis when we're talking about using GLP-1 medications to modify weight. There are probably weight-dependent benefits — pretty easy to understand — things like reducing the mechanical loading especially in lower limb joints like knees and hips, ankles. But there's also this reduction in adipose tissue, and adipose tissue is really an inflammatory organ especially when it's enlarged in obesity and metabolic disease. The fat cells actually release adipokines and cytokines and this can have negative effects on the joint tissues themselves.

So there may be a weight-independent effect and benefit of using GLP-1s, and others including Dr. Frances Berenbaum in France and others in our group have actually shown that the GLP-1 receptor can be expressed and is expressed in
chondrocytes and potentially expressed in chondrocytes and potentially synovial cells, synovial macrophages in synovial cells, synovial macrophages in the joint. So there could even be direct the joint. So there could even be direct benefits of targeting GLP-1 receptors benefits of targeting GLP-1 receptors could be through reduction of innate could be through reduction of innate immune uh signaling, reduction of immune uh signaling, reduction of NF-kappa B signaling and the downstream NF-kappa B signaling and the downstream inflammatory pathways that we know that inflammatory pathways that we know that come from that. So the takeaway is that come from that. So the takeaway is that even though some of that work is still even though some of that work is still pre-clinical, there may be weight pre-clinical, there may be weight independent benefits of using GLP-1s. independent benefits of using GLP-1s.

And where did all this excitement come And where did all this excitement come from? Well, in 2024, um, Blitall and from? Well, in 2024, um, Blitall and colleagues published in the New England colleagues published in the New England Journal the results of the STEP 9 trial, Journal the results of the STEP 9 trial, which was studying semaglutide and its which was studying semaglutide and its benefits compared to placebo up to the benefits compared to placebo up to the 2.4 milligram dose every week in people 2.4 milligram dose every week in people with obesity and knee osteoarthritis. with obesity and knee osteoarthritis. And of course, they showed that there And of course, they showed that there was a weight loss benefit. That part was a weight loss benefit. That part wasn't new, but there was a huge effect wasn't new, but there was a huge effect in reducing pain. It was measured by the in reducing pain. It was measured by the WOMAC pain scale that was actually WOMAC pain scale that was actually developed here in London. The magnitude developed here in London. The magnitude of the benefit, the pain reduction that of the benefit, the pain reduction that was seen is really only ever seen in was seen is really only ever seen in trials of knee arthroplasty, so joint trials of knee arthroplasty, so joint replacement surgery. But we haven't had replacement surgery. But we haven't had trials of medications in osteoarthritis trials of medications in osteoarthritis that have had such a big effect on pain. that have had such a big effect on pain.

It's important to contrast that older It's important to contrast that older studies, including a trial with studies, including a trial with liraglutide, did not show as much of an liraglutide, did not show as much of an effect on pain, but also didn't show the effect on pain, but also didn't show the same magnitude of weight loss benefit. same magnitude of weight loss benefit. And observational data including things and observational data including things like the Shanghai osteoarthritis cohort. like the Shanghai osteoarthritis cohort. Um there's a large trietic study that's Um there's a large trietic study that's been published that showed that the use been published that showed that the use of GLP-1 receptor agonists in particular of GLP-1 receptor agonists in particular in patients who have another indication in patients who have another indication like diabetes can also reduce rates of like diabetes can also reduce rates of joint replacement. So there's a fair bit joint replacement. So there's a fair bit of evidence already to say that the of evidence already to say that the long-term outcomes in people with long-term outcomes in people with osteoarthritis can have uh can be osteoarthritis can have uh can be impacted through the use of GLP-1s. So impacted through the use of GLP-1s. So what do we need to know as what do we need to know as rheumatologists? Now, we're not the first rheumatologists? Now, we're not the first or even the second specialty to be or even the second specialty to be prescribing in this case. Endocrinology, prescribing in this case. Endocrinology, our colleagues in internal medicine, our colleagues in internal medicine, primary care, cardiometabolic primary care, cardiometabolic specialists have years of real world specialists have years of real world experience prescribing this drug class. experience prescribing this drug class.

And so, we need to be learning from And so, we need to be learning from them, not just learning everything from them, not just learning everything from scratch. And tolerability is a is a real scratch. And tolerability is a is a real concern. It can limit use in people who concern. It can limit use in people who are are using GLP-1s. GI side effects are are using GLP-1s. GI side effects like nausea, vomiting, diarrhea, etc. like nausea, vomiting, diarrhea, etc. the most common adverse effects. In the most common adverse effects. In practice, it can definitely limit practice, it can definitely limit adherence and limit the use. But our
adherence and limit the use. But our colleagues in endocrine and others have really shown that there can be mitigation strategies here. Slow titration of the medication and optimizing the dose to the individual can really help to mitigate some of these side effects. We also need to know to screen for contraindications like medullary thyroid carcinoma in the family or the patient themselves.

But I really think co-management is going to be the key for success here. There are going to be other cardiometabolic diseases especially in osteoarthritis that are present also in psoriatic arthritis and so coordinating the care with endocrinology or cardiologists or whoever else is involved in the patient's care is going to be a key success strategy.

There are also going to be times though when the osteoarthritis itself and also even in psoriatic arthritis that the primary motivation for using a GLP-1 agonist is going to actually be to improve the rheumatologic outcome, to improve the arthritis outcome, and in that scenario the rheumatologist may actually be the most appropriate point person or the prescriber, as opposed to another specialist.

What else is coming in this space? There's a lot. So there's new topline results released for the TRIUMPH 4 trial. This is using retatrutide, which is a triple agonist — GLP-1, GIP, and glucagon receptor agonist — a phase 3 RCT in osteoarthritis. It shows huge benefits in terms of pain reduction and weight loss. That has yet to be peer-reviewed but the topline results are out.

There's also the STOP Knee Osteoarthritis trial, which is tirzepatide, a dual GLP-1 and GIP agonist, in patients with knee osteoarthritis and obesity. We're waiting for the results of that. And interestingly, also the inflammation trial, which we're participating in as a site, is actually intraarticular injection of a GLP-1, liraglutide, to see whether you could actually modify pain and inflammation at the level of the joint by giving the medication intraarticularly.

So I just want to close by saying yes, there's a lot more to come here, but we already know that obesity is very modifiable and it is a mechanistic central driver of outcomes in people with osteoarthritis. So we now have tools at our disposal — medical tools including GLP-1 receptor agonists — that really can and have been shown to reduce pain in a clinically meaningful way and hopefully improve outcomes for our patients with osteoarthritis. If you'd like to know more, please go to RheumNow. Thank you so much.