Preeya Alexander: You’ve got another use for a very cost-effective diabetes medication, Metformin.
Norman Swan: Well, not me, but Professor Flavia Cicuttini from the Alfred Hospital and Monash University has. So knee osteoarthritis, incredibly common, lots of knee replacements are being done throughout Australia. Could we delay knee replacements if you actually got in earlier with more effective treatments? And Flavia and her colleagues have just done a randomised trial in people with knee osteoarthritis of a drug called Metformin. It’s cheap, it treats type 2 diabetes normally. Indeed, some people are taking it as an anti-ageing drug, but that’s another story. And the question is, does it help knee osteoarthritis? And we wouldn’t be running this story if the answer wasn’t yes. But the question I put to Professor Flavia Cicuttini, who is at the Alfred Hospital and Monash University, is why on earth did she think that Metformin might be a drug that could help osteoarthritis in the first place?
Flavia Cicuttini: Over the years we showed that knee osteoarthritis is driven by both loading and metabolic factors related to obesity. We realised that Metformin has actually a lot of the actions that counter these metabolic changes.
Norman Swan: Such as?
Flavia Cicuttini: So it has an effect on low grade inflammation. It improves the nutrition and health of joint cartilage, it has a small effect on weight loss, and actually has a potential effect on central pain as well.
Norman Swan: Really? So it affects the brain?
Flavia Cicuttini: That’s right, and the data in animal models supported that Metformin has effects on the immune system in animal models of osteoarthritis, it has effects on the health of the joint cartilage, and there was also some observational data from humans. So we decided to go ahead, because there’s such a lack of effective therapies in osteoarthritis, particularly knee osteoarthritis, apart from exercise, weight loss, Panadol helps a little bit, anti-inflammatories help a little bit. And so we decided to go ahead with the Metformin trial.
Norman Swan: And what did you find?
Flavia Cicuttini: We took people that are overweight and obese and we randomised them to Metformin up to two grams a day, which is a standard dose used for diabetes, or a matched placebo. We followed them for six months and found that there was a reduction in knee pain in the Metformin group.
Norman Swan: You have to say it was a small trial, so you do recommend that it goes to a larger trial. The results were modest. But did the person themselves notice a difference?
Flavia Cicuttini: Yes, a lot of the patients reported feeling a lot better.
Norman Swan: Metformin is not without its side effects. What was the downside in terms of side effects?
Flavia Cicuttini: Metformin has been around for 60 years. Doctors are very familiar with its use. The downside of metformin is that it can cause some abdominal discomfort and diarrhoea. Now, those effects can be reduced significantly by slowly building up the dose. But I think the place for Metformin is that over the last ten years there’s been this quite rapid increase in knee replacements done for early osteoarthritis based on the idea that there’s no treatment for osteoarthritis and that knee replacements last a long time. And at first glance, you might say, oh well, maybe that’s reasonable, but what also I don’t think is well appreciated is that dissatisfaction rates with technically perfect knee replacements are quite high. They vary from 20% to 30%.
Norman Swan: What does that actually mean? So you’ve had a good operation, everything’s gone well, but the person’s not happy. Why are they not happy?
Flavia Cicuttini: They’re not happy because they continue to have pain. Their knee replacement isn’t working in the way they expected it to. So we’re seeing more and more that people are having knee replacements because they can’t go jogging, they can’t do some of the activities they expect that they will be able to do, but knee replacements were never designed to continue doing the more high-level activity that we expect to be able to do. If people are having it because they can’t go on a 10k jog, they’re the sorts of situations where people’s expectations aren’t met, and then people are searching for something else. And so we see people go down the route of platelet rich plasma, but the evidence is that it doesn’t work. Stem cells, which show promise, but there’s no evidence they work.
So where we think the Metformin results have the potential to impact clinical practice is that the Metformin has a different action. It’s not a pain killer, it’s not an anti-inflammatory. The idea would be that the Metformin slowly kicks in, and you would be encouraging the person to keep active, start doing some walking, maybe using supports like walking poles, so that with this increased activity and the Metformin, the person’s pain resolves. Now, if symptoms settle, you don’t need a knee replacement.
Norman Swan: Which brings me finally to the holy grail in osteoarthritis. What’s changed in rheumatoid arthritis, an autoimmune disease, is that over the last 20-odd years, instead of just patching over the surface with steroids and paracetamol and what have you, non-steroidals and the disease progresses, they now have drugs, very expensive drugs, that actually stop the disease or slow it down, called disease modifying agents. Is Metformin a disease modifying agent? Because what orthopaedic surgeons will say to you is, well, you can do all that, but the disease will progress and eventually you’ll be back in my office. Is there any evidence that Metformin could slow the disease itself?
Flavia Cicuttini: First of all, even though the orthopaedic surgeon might quite rightly say, you know, maybe the disease will keep progressing, if we’re able even just delay knee replacements by one, two, three, four years, that has potential huge impact, because at the moment a knee replacement costs $20,000. We discussed the potential for people being dissatisfied if it’s done too early. But if you do it early, then if knee replacements last about 20 years, and they last probably less in very physically active younger people, we know that revision surgery is increasing at the rate of about 14% a year, and the results are not as good. So even if Metformin is able to delay knee replacements by a year or two or three or until the person really needs it, we’re likely to get less unhappiness with the first operation. And if we could just have everybody have only one knee replacement, we would have a lot less suffering and save a huge amount of money.
Norman Swan: Professor Flavia Cicuttini, who’s head of Rheumatology at the Alfred Hospital and the Musculoskeletal Unit at Monash University, both in Melbourne.
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