Med News: Stanford Study Find Metformin Use Is Associated With Lower Incidence Of Osteoarthritis
: A new study led by researchers from Stanford University, California-USA that also included scientists from Chinook Therapeutics, Washington-USA and The VA Palo Alto Health Care System, California-USA has found that metformin use is associated with lower incidence of osteoarthritis.
Osteoarthritis (OA), the most commonly observed type of arthritis, is associated with considerable morbidity. Existing therapeutic options for osteoarthritis are aimed at managing symptoms only, highlighting the need for disease-modifying agents to retard or reverse OA progression.
Metformin, a biguanide-derived substance, is commonly prescribed for T2D, considered safe, and reported to possess anti-inflammatory, anti-aging, anti-cancer, immunomodulatory, analgesic, and weight-lowering properties.
Past research has reported on the protection conferred by metformin use against OA via activating AMP-activated protein kinase signaling, reducing matrix metalloproteinase-13 (MMP-13) levels, enhanced autophagy, decreased apoptosis of chondrocytes, and enhancing mesenchymal stem cells' anti-inflammatory and chondroprotective properties.
However, robust epidemiological-study data are limited. Most studies evaluate the protective effects of metformin against pre-existing OA progression, not considering the simultaneous use of antidiabetic medications and having time-associated bias.
The study aimed to determine the risk of OA and joint replacement in individuals with type 2 diabetes treated with metformin compared with a sulfonylurea.
The retrospective cohort study used claims data from the Optum deidentified Clinformatics Data Mart Database between December 2003 and December 2019.
Study participants included individuals aged 40 years or older with at least 1 year of continuous enrollment and type 2 diabetes. Individuals with type 1 diabetes or a prior diagnosis of OA, inflammatory arthritis, or joint replacement were excluded. Time-conditional propensity score matching was conducted using age, sex, race, Charlson comorbidity score, and treatment duration to create a prevalent new-user cohort. Data were analyzed from April to December 2021. All the participants had been receiving either metformin or a sulfonylurea.
The outcomes of interest were incident OA and joint replacement. Cox proportional hazard models were used to calculate adjusted hazard ratios (aHRs) of incident OA and joint replacement. In a sensitivity analysis, individuals only ever treated with metformin were compared with individuals only ever treated with a sulfonylurea, allowing for longer-term follow up of the outcome (even after stopping the medication of interest).
After time-conditional propensity score matching, the metformin and control groups each included 20 937 individuals (mean [SD] age 62.0 [11.5] years; 24 379 [58.2%] males). In the adjusted analysis, the risk of developing OA was reduced by 24% for individuals treated with metformin compared with a sulfonylurea (aHR, 0.76; 95% CI, 0.68-0.85; P < .001), but there was no significant difference for risk of joint replacement (aHR, 0.80; 95% CI, 0.50-1.27; P = .34). In the sensitivity analysis, the risk of developing OA remained lower in individuals treated with metformin compared with a sulfonylurea (aHR, 0.77; 95% CI, 0.65-0.90; P <&thinsp
;.001) and the risk of joint replacement remained not statistically significant (aHR, 1.04; 95% CI, 0.60-1.82; P = .89).
Metformin treatment reduced new-onset OA risk by 24.0%, compared to sulfonylurea treatment (aHR 0.8).
The incident rate of osteoarthritis for metformin-treated and sulfonylurea-treated individuals for every 1000 individual years were 28 and 40, respectively.
The corresponding incident rates for joint replacement for every 1,000 individual years were 1.5 and 2.1, respectively. In the sensitivity analysis, the incident rates of osteoarthritis for metformin-treated and sulfonylurea-treated individuals were 25 events and 31 events for every 1,000 individual years, respectively.
The study team found a 23.0% decrease in risk of OA development following metformin treatment, compared to sulfonylurea treatment (aHR 0.8). Compared to sulfonylurea treatment, the observed therapeutic benefit conferred by metformin treatment was lower among sulfonylurea-treated individuals with previous metformin exposure compared with sulfonylurea-treated individuals without previous metformin exposure. The finding could be since sulfonylurea-treated individuals with previous metformin exposure derived long-term protection related to metformin exposure.
The study findings conclude that in this cohort study of individuals with diabetes, metformin treatment was associated with a significant reduction in the risk of developing OA compared with sulfonylurea treatment. These results further support preclinical and observational data that suggest metformin may have a protective association against the development of OA; future interventional studies with metformin for the treatment or prevention of OA should be considered.
The study findings were published in the peer reviewed journal: JAMA Network Open.
Overall, the study findings showed that in the cohort of T2D patients, metformin use significantly decreased OA development risks compared to sulfonylurea medications. The findings underpin preclinical (in macaques, mice, and rats) data and observational study (in humans) data on the protective effects of metformin against new-onset OA.
However, the study findings should be cautiously interpreted due to missing body mass index (BMI) data and the probability that metformin-induced weight loss could have led to the study findings. Therefore, further research on metformin therapy for OA prevention or treatment must be conducted.
Past Med News
and human data also support the use of metformin for the treatment or prevention of OA.
In one observational study, individuals with obesity and knee OA who were treated with metformin were found to have a lower rate of medial cartilage volume loss compared with individuals not treated with metformin.
A population-based cohort study reported a reduced incidence of total knee arthroplasty in individuals with preexisting OA and diabetes who had received a combination of metformin and a cyclooxygenase-2 inhibitor compared with a cyclooxygenase-2 inhibitor alone.
Additional cohort studies have found that individuals with diabetes treated with metformin had a significantly reduced risk of total knee arthroplasty.
A systematic review of 10 preclinical and 5 human studies of OA concluded that metformin had chondroprotective, immunomodulatory, and analgesic associations.
The current study findings provide further, robust epidemiological evidence that metformin may be associated with protection in the development and progression of OA in individuals with type 2 diabetes.
The study team concluded, “In this large, nationwide cohort study of individuals with diabetes, metformin treatment was associated with a significant reduction in the risk of developing OA compared with sulfonylurea treatment. Results from this study must be interpreted with caution due to the lack of data on body mass index, and the possibility that weight loss induced by metformin may have accounted for some of the benefit seen. Despite this limitation, this study further supports the preclinical and observational data that show metformin may have a protective association against the development of OA. Future interventional studies with metformin for the treatment or prevention of OA should be considered.”
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