Effect of metformin use on risk of total knee arthroplasty in patients with knee osteoarthritis combined with diabetes and/or obesity

Abstract

Purpose: Metformin (MET) is a first-line drug for type 2 diabetes, and metabolic mechanisms including reduced hepatic gluconeogenesis and insulin production are thought to underlie this effect. In recent years, epidemiological studies have found that in addition to lowering blood glucose, MET can reduce the incidence and mortality of cancer, improve intestinal microbiota, reverse the effects of aging and has anti-inflammatory effects. These effects make MET a popular investigational drug in obesity and age-related diseases. Studies have found that the pathogenesis of obesity-related osteoarthritis (OA) is not only related to mechanical loading, but also mediated by inflammatory and metabolic mechanisms. Recent studies have suggested that the imbalance of intestinal flora in obesity and metabolic syndrome is related to the onset of OA. It was also found that gut microbiota produces the intermediate agmatine which is a regulator of MET effect on host lipid metabolism and longevity. Theoretically, MET may play a potential therapeutic role targeting obese OA by regulating inflammatory factors, metabolic factors and intestinal flora. However, clinical studies evaluating the effect of MET on knee OA patients combined with diabetes and/or obesity are rare. Therefore, the purposes of this study was to examine whether MET use was associated with reduced risk of total knee arthroplasty (TKA) in knee OA individuals combined with diabetes and/or obesity. Methods: Participants with knee OA who were also diagnosed obesity (body mass index [BMI]≥30kg/m2) and/or diabetes between 10/6/2000 to 15/7/2019 were selected from Hospital Information System of Zhujiang Hospital. Participants were classified as MET users if they were recorded using MET in the doctor’s advices or self-reported regular MET users (n = 300). Non-users of MET were defined as participants who did not report the use of MET at medical history recording or at the doctors’ advices (n =579). TKA status was assessed using the operation note. Effusion and meniscus status were assessed using magnetic resonance imaging reports. Logistic regression model were used for statistical analyses. Results: A total of 879 participants were included in current study. MET non-users (n = 579, 66%) were significantly older than MET users (p < 0.05). No significant differences between groups were found in terms of gender, body mass index (BMI), Non-Steroid Anti-Inflammatory Drugs (NSAIDs) usage, effusion and meniscal status. The risk of TKA was significantly lower in MET users compared with non-users (6.0% vs. 11.4% ), with Odds Ratio of 0.49 (95% CI, 0.29 to 0.85, p = 0.01), after adjustment for age, gender, BMI, tramadol, sodium hyaluronate (SH) and steroids uses. Compared with MET and tramadol non-users, MET alone was associated with reduced risk of TKA (OR = 0.48, 95% CI, 0.25 to 0.93, p = 0.03). Compared with MET and intra articular injection of sodium hyaluronate non-users, MET alone was associated with reduced risk of TKA (OR = 0.54, 95% CI, 0.31 to 0.94, p = 0.03). Compared with MET and intra articular injection of steroids non-users, MET alone was associated with reduced risk of TKA (OR = 0.51, 95% CI, 0.29 to 0.89, p = 0.02). Conclusions: These data suggest that using metformin alone may attenuate the risk of TKA in those with knee OA and diabetes or obesity. Randomized controlled trials are required to confirm whether metformin could be a potential disease-modifying drug for knee OA.Tabled 1Table 1. Characteristics of study participantsNo Met (n=579)Met (n=300)P*Age, years74.1 ± 10.372.6 ±10.30.049Female, n(%)429 (74.1)216 (72.0)0.506BMI,kg/m226.1 ± 3.826.2 ± 4.40.892Celebrex, n(%)210 (36.3)120 (40.0)0.279Etoricoxib, n(%)112 (19.3)48 (16.0)0.224Parecoxib, n(%)98 (16.9)31 (10.3)0.009Tramadol, n(%)54 (9.3)17 (5.7)0.059Dolantin, n(%)18 (3.1)8 (2.7)0.714SH, n(%)71 (12.3)43 (14.3)0.387Steroids, n(%)67 (11.6)28 (9.3)0.311Meniscus injury, n(%)44 (7.6)24 (8.0)0.833Effusion, n(%)48 (8.3)26 (8.7)0.849TKA, n(%)66 (11.4)18 (6.0)0.010Data presented as mean (standard deviation) or number (%); BMI, body mass index; TKA, total knee arthroplasty; *For the difference between metformin users and non-users using independent samples t-tests or chi-square tests Open table in a new tab Data presented as mean (standard deviation) or number (%); BMI, body mass index; TKA, total knee arthroplasty; *For the difference between metformin users and non-users using independent samples t-tests or chi-square tests