Can Metformin Lower Need for Joint Replacement in Diabetes?

Metformin may help reduce risk for total joint replacement in patients with type 2 diabetes (T2D), data suggest.

Dr Changhai Ding

Over a 24-month follow-up period, metformin use was associated with a 30% decrease in the risk of total knee and hip replacements, according to Changhai Ding, MBBS, MMed, MD, associate director of the Menzies Institute for Medical Research at the University of Tasmania in Hobart, Australia, and colleagues.

“Randomized controlled clinical trials in patients with osteoarthritis are warranted to determine whether metformin is effective in decreasing the need for joint replacement,” wrote the investigators.

Their findings were published online December 19 in the Canadian Medical Association Journal.

Low Doses Beneficial

The investigators identified patients diagnosed with T2D from 2000 to 2012 in the Taiwan National Health Insurance Research Database and compared those who used metformin with those who did not. They used prescription time-distribution matching and propensity-score matching to balance potential confounders between users and nonusers.

The study included 20,347 metformin-treated participants and 20,347 nonusers. The mean age at baseline was 63 years, and 49.8% of participants were women. Metformin users tended to have more severe diabetes. Common comorbidities in the cohort included hypertension and hyperlipidemia, but only about 16% in both groups had osteoarthritis. At baseline, participants also used various analgesics, as well as other diabetes drugs ranging from sulfonylureas to insulin.

Compared with nonusers, metformin users had had a 30% lower risk of total knee or hip replacement (adjusted hazard ratio [HR], 0.70). The incidence of total knee replacement among metformin nonusers and users was 4.15 per 10,000 person-months and 2.96 per 10,000 person-months, respectively. The incidence of total hip replacement was 0.83 per 10,000 person-months in nonusers and 0.44 per 10,000 person-months in users.

By joint type, the adjusted HR was 0.71 for total knee replacement and 0.61 for total hip replacement among metformin users.

The effect was observed at daily doses of less than 1 g, as well as daily doses of 1 g or more. “This suggests that metformin at a lower dosage could have effects on osteoarthritis,” Ding told Medscape Medical News. “Metformin is a safe, well-tolerated oral medication, even at higher but routinely used dosages. Therefore, for initial clinical trials, we still recommend the efficacy of metformin at routine dosages on knee osteoarthritis. If the effects are confirmed, we may explore whether a lower dosage of metformin is effective.”

Similar results emerged from propensity-score matching analyses and sensitivity analyses of 10,163 participants in each treatment group using inverse probability-of-treatment weighting and competing risk regression.

The biological mechanisms linking metformin and osteoarthritis have yet to be clarified, Ding explained. “Multiple mechanisms may be involved, including anti-inflammation, sustaining adenosine 5′-monophosphate-activated protein kinase activity in chondrocytes and dorsal root ganglia, and regulating metabolism.”

A previous study suggested an association between metformin and reduced annual loss of medial cartilage volume, and another found an association between metformin and reduced joint replacement surgery, said Ding. But another study reported no significant association between metformin use and osteoarthritis risk in patients with T2D. Recently, a retrospective cohort study by Li et al found that metformin users with diabetes had a 19% lower risk for total knee replacement than nonusers.

Ding’s group has begun a randomized clinical trial to see whether metformin can alleviate tibiofemoral cartilage volume loss in overweight patients with osteoarthritis.

No Uniform Indications

Commenting on the current findings for Medscape, Grace Hsiao-Wei Lo, MD, an assistant professor of immunology, allergy, and rheumatology at Baylor College of Medicine in Houston, Texas, called the observational study “thought-provoking.” She had concerns about the way it was conducted, however, including the potentially problematic features of the small percentage of the T2D cohort who had osteoarthritis. Another concern was the fact that the investigators only examined metformin, although patients used various other diabetic and analgesic drugs that might have had an effect. Metformin’s effect on osteoarthritis may result partly from its modest weight-loss effects, said Lo, who was not involved in the study.

Dr Grace Hsiao-Wei Lo

“Another issue with the study is that there is no set indication of the need for total knee or hip replacement. Each surgeon has a different standard,” she added. “And there’s lots of evidence that replacements are largely dependent not on need but on the interest of participants. “So, it’s not necessarily that a patient needs total joint replacement, it’s that they want it.”

Observational studies like this one are a long way from getting us to the prescribing of metformin specifically to prevent or mitigate osteoarthritis, David T. Felson, MD, MPH, a rheumatology researcher and a professor of medicine at Boston University, Boston, Massachusetts, told Medscape. Felson was not involved in the study.

Dr David Felson

“The drug’s mechanisms in osteoarthritis are still unclear. Its effect may be related to adenosine 5′-monophosphate-activated protein kinase activity,” he said. “The drug has pleiotropic effects and is safely used to treat other diseases such as polycystic ovarian syndrome. It may have antisenescence properties, since it’s been shown to extend life a bit in animals.” That said, Felson added, “Like statins, it’s not going be added to the drinking water anytime soon!”

This study was supported by the National Natural Science Foundation of China, Guangzhou Science and Technology Program, Guangdong Basic and Applied Basic Research Foundation, and Wu Jieping Medical Foundation Program. Ding, Lo, and Felson reported no competing interests.

CMAJ. Published online December 19, 2022. Full text.

Diana Swift is a freelance medical journalist based in Toronto, Ontario, Canada.

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