I see so many patients at the clinic who, as they get older, start experiencing pain in their joints from arthritis. It’s so difficult because there haven’t been many great options to help. But a new study just came out that looked at repurposing an extremely common and dirt-cheap medication to treat arthritis. The results are impressive, but there are some caveats. So we’ll look at that study and what you need to know if you or someone you love is dealing with arthritis.
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The New Study
The new study focused specifically on knee osteoarthritis [1]. Osteoarthritis is when the cartilage in our joints breaks down. It’s the most common type of arthritis. Knee osteoarthritis is a painful condition that affects 365 million people worldwide [1]. And we don’t presently have many effective ways to treat it.
But the condition is often connected with being overweight [1]. Why? Part of the reason is obvious. If we’re carrying more weight, that puts more wear and tear on our knee joints. But there’s more to it than that. Obesity also promotes systemic inflammation, and it comes along with problems with how our bodies regulate blood sugar. These other factors together damage and break down cartilage [1].
So here’s what researchers behind this new study wondered: There’s a common medication we’ve used for decades that reduces inflammation, improves blood sugar control, and promotes weight loss. It looks like it addresses the main drivers of arthritis in the knee. Could it help treat this condition for those who are overweight?
The medication is metformin. Researchers designed a randomized, double-blind, controlled study to find out if it would help. Participants got either metformin or a placebo for 6 months. Before and after the study, they asked participants to rate their pain on a visual scale that went from 0 to 100.
At the end, they checked to see how levels of pain had changed [1]. In the metformin group, the pain measurement dropped by just over 31 points, whereas the placebo group dropped by 19 points. Note the placebo effect here, where the placebo group also had improvements in their pain, but the metformin group had greater improvements.
They also used a different kind of test to look for improvements in pain, stiffness, and joint function [1]. They saw positive results here as well for metformin compared to placebo.
But while exciting, there are a few caveats.
First, let’s put the results in perspective. How significant was the pain reduction? Recall that the visual pain scale had 100 points. The average score before the trial began was about 60. So that drop of over 30 cut the pain in half for the group taking metformin. But this isn’t the full picture. We need to compare this to the group taking the placebo. Their pain scores also fell significantly. They went from about 60 to 40 [1].
So metformin improved the pain from knee osteoarthritis by just over 11 points more than placebo. Researchers were looking for a difference of at least 15 between the groups. The results didn’t quite hit that. But metformin did make a bigger difference than using anti-inflammatory medications like ibuprofen or Celebrex in a separate study, which is a significant point [1].
The second caveat is that this improvement for arthritis pain is potentially driven by metformin’s weight loss effect. We’ll come back to that a bit later in this article.
The study ends on a cautiously hopeful note. These results point to a meaningful benefit from metformin, but the sample size was small. We’ll want a larger, and probably longer, clinical trial to get a clearer picture [1].
So if you or a loved one suffers from knee arthritis, should you start taking metformin even if you don’t have diabetes? Like most things in medicine, the answer isn’t black and white, and we need nuance. Here’s the approach that I’ll take with my patients.
I’ll first explain that a longer trial would be helpful. Researchers in this case noted no benefit at 3 months, but there was a benefit at 6 months [1]. Given the mechanisms involved, this makes sense. We’d expect metformin to have an impact that shows up more and more over the long run. So this experiment only gives us a relatively short snapshot.
But an earlier cohort-based study gives us some reason to be optimistic about what a longer study would find. It followed a group of obese patients with osteoarthritis in the knee for 4 years. They checked the volume of knee cartilage using an MRI at the beginning and end of the study. The metformin users had a rate of cartilage loss about half that of non-users [2].
So we have some intriguing evidence that metformin can help relieve arthritis in the knee for people who are overweight. But, again, we need further evidence before we can be confident about the size of the benefit. And it also isn’t clear yet what’s driving the benefit.
As I mentioned above, metformin is known for its anti-inflammatory effects [3]. So is that why it helps with arthritis? Well, as mentioned earlier, metformin also has a weight loss effect, so we need to look at what happened to participants’ weight in the study. The average weight loss in the metformin group was 1.8 kg, compared to 1.2 kg in the placebo group [1].
So the metformin group lost 0.6 kg more. But that amount probably isn’t clinically significant in this context. Studies have found that a loss of about 5% can provide some relief in obese patients with knee arthritis, while 10% is needed for significant relief [4]. So weight loss may have made a small contribution, but probably other effects were more important here.
I’d explain to my patients that we just aren’t sure at this point exactly how metformin is working to help improve knee arthritis pain. It might be to do with its anti-inflammatory effect, but there’s still a lot we don’t know.
So does it make sense to take it to help manage this condition if we don’t know exactly how metformin is providing the potential benefit? Well, if the patient sitting in front of me has type 2 diabetes, I’ve probably already prescribed metformin. In that case, they would receive any benefits for their knees anyway.
Other potential benefits
But what if my patient isn’t diabetic but they are overweight and experiencing arthritis in their knees? Is metformin a good idea?
Again, we need nuance and to discuss the benefits vs risks. There are two other potential benefits that count in its favor. Then we’ll come to two potential concerns.
The first benefit is that metformin can help with weight loss, as already mentioned. And besides decreasing the strain on our joints, weight loss is important for overall health. A large recent cohort study showed that a BMI over 30 was associated with a much higher risk for all-cause mortality [5].
But how much can metformin actually help? Most of the research we have on metformin is confined to those with diabetes. However, there was a large study called the Diabetes Prevention Program trial that focused on those who were at risk of developing diabetes. The study had three groups. One made significant lifestyle changes, the second took metformin, and the third group took a placebo. The metformin group lost 2.1 kg (4.6 pounds) on average over about 3 years [6].
Interestingly, after a 10-year follow-up, the metformin group showed a unique advantage. While the lifestyle intervention group slowly regained weight, the metformin group kept it off [7]. A more recent meta-analysis looked at 21 different trials of metformin in various populations. Taking the results together, metformin was associated with a modest reduction in BMI of about 1 point [8].
So how does metformin help with weight loss? The primary driver seems to be that it lowers the amount of glucose the liver puts out [9]. It also appears to decrease our appetite. An early study found that people taking it voluntarily ate less and felt less hunger [10]. Metformin has even been shown to boost production of glucagon-like peptide 1 (GLP-1), the same substance medications like Ozempic mimic [9]. Among other effects, GLP-1 slows digestion and increases feelings of fullness.
This similarity of action makes metformin a good option for people if Ozempic or other GLP-1 medications aren’t in the budget. The weight loss effects aren’t nearly as large, but they’re real and helpful. And metformin’s weight loss effect starts to become clinically meaningful at a dose of 1,500 mg or higher, which is in line with the 2,000 mg dose used in the new arthritis and metformin trial.
The second potential benefit of metformin for those without type 2 diabetes is more controversial. You’ll see claims online that it can slow our aging and increase our lifespan [11]. Initial interest in metformin as a way to extend life was driven by a number of effects that are relevant to the aging process. Metformin reduces inflammation, helps control insulin levels, and combats oxidative stress [12].
Does the evidence back up the use of metformin to extend lifespan? There is at least some observational evidence that links metformin with the prevention of cancer and age-related decline [13]. So researchers decided to test metformin directly for its life-extending effects through the Interventions Testing Program, using rodent studies. When they tested metformin, they found no impact on lifespan [14].
But what about human studies? A recent review of existing studies found no compelling evidence that it extends lifespan. It does, however, reduce early mortality due to diseases like diabetes [15]. Another large study followed adults at high risk for diabetes, but who didn’t have it at the time the study started, for 21 years. Researchers concluded taking metformin did not affect all-cause mortality or death rates from cancer or heart disease [16].
The case isn’t closed yet, however. There’s a massive ongoing study called Targeting Aging with Metformin (TAME) that’s enrolling 3,000 older adults who will be followed for 6 years to see if metformin helps delay the development or progression of age-related chronic diseases [17].
Should we all be taking this?
I’ll be very interested to see the findings of that trial. But for now, we don’t have strong evidence for metformin’s benefits in this area. And we do have some evidence of potential problems that I share with my patients.
One relates to exercise. In a 2019 study where both groups were exercising, the people who took metformin improved their cardiovascular fitness by only half as much as those who took a placebo [18]. That study was backed up by a 2022 study showing the same thing, with metformin use reducing VO2 max improvements by half [19].
These effects are a big deal. If we’re taking something that blunts the benefits of exercise, we’re undercutting one of our most effective tools for ensuring a healthier, longer life. That’s why I include TMG in MicroVitamin to help boost exercise performance.
A second problem with metformin is about testosterone. A study found that metformin lowers testosterone levels in men [20]. Why is this a concern? Because lower testosterone levels are associated with a higher risk of death, especially among older men [21].
So let’s return to the question: Does it make sense for my patients to take metformin if they aren’t diabetic? The argument in its favor goes like this: metformin has established benefits when it comes to things like inflammation, weight loss, and — now — arthritis in the knees for overweight individuals. It’s been in use for decades and has a good safety profile. Any adverse effects are usually temporary and can often be avoided by starting with a low dose and gradually increasing it [21]. And it’s cheap. You can get a month’s supply of the dose used in the arthritis study — 2,000 mg a day — for just $6.14 at CostPlus Drugs [22].
On the other hand, the data is preliminary when it comes to arthritis. There are also the worries about exercise and testosterone.
So for my patients with type 2 diabetes, the decision is relatively easy that we’d start metformin. But for non-diabetics who are overweight and have painful knees, the answer isn’t quite as clear-cut. Whenever I prescribe a medication, I have to make sure that the benefits vastly outweigh the risks. I present those benefits and risks to my patients, and if they decide that the potential benefits for their pain outweigh the potential risks with metformin, then I’d consider prescribing it based on this new study.
Reference List
1. https://jamanetwork.com/journals/jama/article-abstract/2833338
2. https://arthritis-research.biomedcentral.com/articles/10.1186/s13075-019-1915-x
3. https://pmc.ncbi.nlm.nih.gov/articles/PMC10680465/
4. https://pmc.ncbi.nlm.nih.gov/articles/PMC4238740/
5. https://pmc.ncbi.nlm.nih.gov/articles/PMC10321632/
6. https://pmc.ncbi.nlm.nih.gov/articles/PMC1370926/
7. https://pubmed.ncbi.nlm.nih.gov/19878986/
8. https://journals.sagepub.com/doi/10.1177/2042018820926000
9. https://pmc.ncbi.nlm.nih.gov/articles/PMC6520185/
10. https://onlinelibrary.wiley.com/doi/10.1002/j.1550-8528.1998.tb00314.x
11. https://fortune.com/well/2023/05/04/metformin-anti-aging-longevity-risks-side-effects/
12. https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1330797/full
13. https://pmc.ncbi.nlm.nih.gov/articles/PMC6779524/
14. https://pmc.ncbi.nlm.nih.gov/articles/PMC5013015/
15. https://pubmed.ncbi.nlm.nih.gov/34421827/
17. https://www.afar.org/tame-trial
18. https://pmc.ncbi.nlm.nih.gov/articles/PMC6351883/
19. https://pmc.ncbi.nlm.nih.gov/articles/PMC9321693/
20. https://pmc.ncbi.nlm.nih.gov/articles/PMC8740051/
21. https://pmc.ncbi.nlm.nih.gov/articles/PMC9938530/
22. https://www.costplusdrugs.com/medications/metformin-1000mg-tablet/
