Study shows that antidiabetics can reduce the risk of osteoarthritis

In a study recently published in The Lancet EBioMedicineA team of scientists used Mendelian randomization analyses to investigate whether antidiabetic drugs could potentially be used as disease-modifying osteoarthritis drugs or DMOADs for the therapeutic treatment of osteoarthritis.

Study: Investigation of antidiabetic drug targets as potential disease-modifying agents in osteoarthritisPhoto credit: Peter Porrini/Shutterstock.com

background

Osteoarthritis is a disease that affects the joints and is characterized by the progressive degradation of cartilage in the joints, inflammation, and subchondral bone remodeling. Various biochemical processes and biomechanical forces contribute to the etiology of this common form of arthritis.

Despite the pain and morbidity of osteoarthritis, which contribute significantly to limitation of normal function and disability, there are no effective DMOADs to delay or reverse the progression of joint degeneration.

However, recent research has shown that metabolic disorders can contribute significantly to the progression of the disease, suggesting an interplay between osteoarthritis and metabolic syndromes.

Evidence from interactions at the local and systemic level indicates that hyperglycemia may influence osteoarthritis. In addition, the accumulation of end products of glycation and oxidative stress is thought to contribute to cartilage damage.

These findings underscore the potential of antidiabetic drugs to influence or alter the pathways responsible for joint health.

About the study

In the present study, researchers used a Mendelian randomization approach that uses genetic variants in the form of single nucleotide polymorphisms (SNPs) to investigate causal relationships and determine whether antidiabetic drugs could play a potential role as DMOADs.

Previous studies investigated the effects of metformin on osteoarthritis and concluded that the drug can modulate cartilage matrix homeostasis and control inflammatory responses.

Other studies on another class of antidiabetic drugs, glucagon-like peptide-1 receptor agonists (GLP1-RA), have also reported promising results in the treatment of osteoarthritis.

Here, the scientists used Mendelian randomization to test whether the target molecules of antidiabetic drugs are also involved in the development of osteoarthritis and to explore the potential of antidiabetic drugs to modify osteoarthritis progression.

Pharmacological databases were used to identify the genetic targets of the types of antidiabetic drugs that are in clinical use. The results from genome-wide association studies conducted on the UK Biobank population were then used to obtain the instrumental variables or SNPs.

This step helped to identify the instrumental outcome variables for the seven main antidiabetic drugs, namely alpha-glucosidase inhibitors, GLP1-RAs, insulin and insulin analogues, metformin, sodium-glucose cotransporter 2 inhibitors or SGLT2i, sulfonylureas and thiazolidinediones.

Summary statistics from some of the most recent and comprehensive genome-wide analysis studies have been used to examine osteoarthritis phenotypes such as hip and/or knee osteoarthritis, hand osteoarthritis, knee osteoarthritis, finger osteoarthritis, hip osteoarthritis, spine osteoarthritis, thumb osteoarthritis, early-onset forms of osteoarthritis, total joint replacement, total hip or knee replacement, or osteoarthritis at other sites.

Subsequently, a two-sample Mendelian randomization was performed to determine the causal effect of each genetic proxy of antidiabetic drug targets on osteoarthritis phenotypes.

Focusing on genetic proxies rather than blood sugar levels helped to distinguish between regular changes in blood sugar levels and the effect of antidiabetic drugs.

Mendelian randomization analyses were adjusted for covariates such as smoking status, blood pressure, alcohol consumption, and body mass index. In addition, gene expression and colocalization analyses were performed to determine the association between gene expression related to the antidiabetic drug and osteoarthritis risk.

Results

The study found that antidiabetic drugs may play a therapeutic role in slowing the progression of osteoarthritis.

Many of the antidiabetic drug targets showed a significant association with the consequences of osteoarthritis, suggesting that metabolic derangement may be one of the underlying factors in the pathogenesis of osteoarthritis.

However, the results also showed that sulfonylurea-based antidiabetics could increase the risk of osteoarthritis. Sulfonylureas target the KCNJ11 Gene encoding the four subunits of the adenosine triphosphate (ATP)-sensitive potassium channel in the membranes of pancreatic beta cells.

This subunit plays a protective role in osteoarthritis and its inhibition by sulfonylureas increases the risk of osteoarthritis.

This was further supported by the finding that the expression of KCNJ11 was observed mainly in myocytes and skeletal muscles, and serum analyses of osteoarthritis patients showed a downregulation of KCNJ11 gene expression.

The results confirmed the beneficial effects of GLP1-RAs and metformin in reducing the risk of finger and knee osteoarthritis and supported the beneficial effects of metformin in chondroprotection, pain relief and modulation of immune responses.

Conclusions

Overall, the study found that some antidiabetic drugs such as sulfonylureas may increase the risk of osteoarthritis, while GLP1-RAs and metformin have a beneficial effect in reducing the risk of various osteoarthritis phenotypes due to their immunoregulatory, anti-inflammatory and chondroprotective properties. These findings support the potential use of antidiabetic drugs as DMOADs.