Development of Osteoarthritis in Adults With Type 2 Diabetes Treated With Metformin vs a Sulfonylurea

Key Points Question Is metformin use associated with incidence of osteoarthritis (OA)? Findings In this cohort study including 41 874 time-conditional propensity score–matched patients using metformin or a sulfonylurea, those treated with metformin had a lower estimated risk of developing OA. Meaning These findings suggest that metformin use was associated with a lower incidence of OA, and future interventional studies with metformin for preventing OA could be considered.


Introduction
Osteoarthritis (OA) is the most common form of arthritis, affecting more than 32.5 million individuals in the United States, and it is one of the major contributors to global years lived with disability. [1][2][3] Current therapeutic strategies for OA are focused on symptomatic management, and there are no effective disease-modifying treatments to halt, slow, or reverse the progression of OA. 4 This represents a large unmet need.
Metformin is a biguanide derivative that is used as first-line treatment of type 2 diabetes by inhibiting hepatic gluconeogenesis and increasing muscle insulin sensitivity. 5 Metformin is generally considered safe in most patient populations and is available at a low cost. 6 In addition to its primary role in the treatment of diabetes, metformin has been purported to have anti-inflammatory, antiaging, anticancer, pro-weight loss, and immunomodulatory effects. 7 Emerging evidence suggests that metformin may be useful for the treatment or prevention of OA. [8][9][10][11][12][13][14][15] Preclinical studies suggest that metformin has disease-modifying properties in OA models in mice, rats, and macaque monkeys. 9,10 Observational studies in humans have also largely supported the use of metformin associated with preventing the development of OA or the need for joint replacement. 8,[13][14][15] However, these studies have predominately focused on progression of preexisting OA (as opposed to the development of incident OA); many have not accounted for concomitant antidiabetic medication use, thus failing to fully isolate the effects of metformin; and some have suffered from immortal time bias related to the comparison of metformin users and nonusers (as opposed to an active treatment control arm).
Based on the available preclinical and observational human data, metformin use may prevent the development of OA. Therefore, we conducted a large, nationwide cohort study using timeconditional propensity score matching to evaluate the risk of developing OA and the need for joint replacement in individuals with diabetes who were treated with metformin compared with a sulfonylurea.

Methods
This cohort study was deemed exempt from review and informed consent by the Stanford University institutional review board because data were deidentified. This study adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cohort studies.

Study Design and Data Source
This was a retrospective cohort study using data from the Optum Clinformatics Data Mart Database (CDM), a deidentified database derived from a large, adjudicated claims data warehouse, from December 1, 2003, to December 31, 2019. This data set includes more than 15 million individuals annually from across the United States who are privately insured or Medicare Advantage Part D members. This provides a geographically representative sample; however, it does not include recipients of Medicaid, and thus the resulting study population has a higher socioeconomic status than the total population with diabetes at risk for OA. with type 1 diabetes, patients with the first diagnosis of diabetes occurring after the start date of metformin or the sulfonylurea, patients started on metformin and a sulfonylurea at the same time, and patients using combination metformin or sulfonylurea medications. Individuals with prior diagnoses of OA or any inflammatory arthritis or with joint replacement based on Current Procedural Terminology (CPT) codes prior to the index date or within the first 90 days of the index date were also excluded (eTable 1 in Supplement 1). The lookback period for these exclusion criteria included all available data.

Exposure
The exposed group included individuals with diabetes treated with metformin for at least 90 days, and the control group included individuals with diabetes who were treated with a sulfonylurea medication for at least 90 days. Those who were initially treated with metformin and then switched to a sulfonylurea could contribute data to both groups. People who switched to metformin after being treated with a sulfonylurea contributed data to the sulfonylurea group and were then censored when switching. This was done to maximize the number of individuals contributing data to the sulfonylurea group, which was substantially smaller in size compared with the metformin group.

Outcome Ascertainment
The primary end point was the time to diagnosis of incident OA starting 90 days after the index date.
Ninety days was chosen as the minimum period of time in which a treatment effect was likely to be observed. OA was defined as 2 or more ICD-9 or ICD-10 codes for OA separated by 14 days or more. 18 The secondary end point was the time to joint replacement starting 90 days after the index date.
Joint replacement was defined as a documented CPT code for hip or knee joint replacement.
Individuals were followed from 90 days after the index date until they received a diagnosis of OA, underwent knee or hip joint arthroplasty, stopped treatment with metformin or a sulfonylurea (defined as the start of a gap of 90 days or more with no treatment), received any diabetes treatment other than metformin or a sulfonylurea, were no longer present in the Optum CDM database, or until the end of the follow-up period (December 31, 2019) (eFigure 1 in Supplement 1).

Statistical Analysis
Given that sulfonylureas are often used as second-line agents after metformin, there may be inherent biases in the comparison of individuals treated with metformin and individuals treated with a sulfonylurea. For this reason, we compared these 2 groups using a prevalent new-user cohort design (eFigure 2 in Supplement 1). 19 This allowed us to compare the first-line treatment (metformin) with the second-line treatment (sulfonylurea) using time-based exposure sets to identify matched individuals at the same point in the course of disease, thus helping to eliminate potential time-lagging bias. 20 The cohort included all individuals treated with a sulfonylurea. For each person treated with a sulfonylurea, a matched person treated with metformin was identified based on time-based exposure sets defined as time intervals (±15 days) from the first prescription of metformin to the first dose of sulfonylurea. Individuals were matched 1:1 on time-conditional propensity scores using conditional logistic regression adjusting for age, sex, race and ethnicity (reported in the database as Asian, Black, Hispanic, White, or unknown), Charlson comorbidity score, and treatment duration to estimate the propensity to receive a sulfonylurea. Race and ethnicity were included in analyses because racial differences in OA prevalence and severity may exist. 21 For time-conditional propensity score matching, we started chronologically with the first individual prescribed a sulfonylurea and selected the individual from the exposure set with the closest time-conditional propensity score.
Once a person had been selected into the comparator group, they were no longer considered in subsequent exposure sets as potential comparators.
Baseline characteristics of individuals in both groups after time-conditional propensity score matching were compared. We used the Quan-Deyo method to calculate the Charlson comorbidity score. 22 Standardized mean differences (SMDs) were calculated using the tableone package in R Cox proportional hazard models were used to assess the hazard ratio (HR) and 95% CI of developing OA and joint replacement among individuals with diabetes treated with metformin compared with a sulfonylurea after adjusting for age, sex, race and ethnicity, geographical region, education, Charlson comorbidity score, and outpatient visit frequency. IRs were reported as the number of events per 1000 person-years. Kaplan-Meier curves were created to report the probability of developing OA over a certain time interval. A stratified analysis was conducted using the matched data to evaluate the treatment outcomes of metformin compared with a sulfonylurea. The results

JAMA Network Open | Diabetes and Endocrinology
were stratified by the matched pairs for individuals treated with a sulfonylurea with prior metformin exposure and those without prior metformin exposure.
All statistical analyses were conducted using SAS version 9.4 (SAS Institute) and R version 4.1.1.
Charlson comorbidity scores were calculated using the icd package. 23 All 95% CIs and P values were based on 2-sided hypothesis tests, where P < .05 was considered statistically significant. The statistical analysis plan is presented in the eAppendix in Supplement 1. Data were analyzed from April to December 2021.
The robustness of our results was examined through a sensitivity analysis comparing individuals treated with metformin with individuals treated with a sulfonylurea who were only ever treated with those medications (eFigure 1 in Supplement 1). This allowed for longer-term follow-up of the outcome even after people had stopped the medication of interest, since with this analysis, no new medications could subsequently be introduced that could influence the outcome of interest. For both groups, the index date was the first fill date for the drug of interest. For the exposed group, we included individuals with diabetes who were ever treated with metformin and never treated with any additional diabetes medications during their entire follow-up period. For the control group, we included individuals with diabetes who were ever treated with a sulfonylurea medication and never treated with any additional diabetes medications during their entire follow-up period. We excluded people who ever received any diabetes medication other than metformin or a sulfonylurea (including combination metformin or sulfonylurea medications). We conducted 1:1 propensity score matching of individuals in the exposed group and individuals in the control group using the same variables as in the primary analysis. We used a caliper of width equal to 0.2 of SD of the logit of the propensity score. 24,25 Results

Patient Characteristics
After time-conditional propensity score matching, 20 937 individuals were included in each group

Primary Outcome
Using a prevalent new-user cohort design and after time-conditional propensity score matching, the IR of OA for individuals treated with metformin was 27.5 events per 1000 person-years, compared with 39.6 events per 1000 person-years for individuals treated with a sulfonylurea ( the follow-up period of more than 6 years (Figure).

Secondary Outcome
In the prevalent new-user cohort analysis, the IR of joint replacement for individuals treated with metformin was 1.5 events per 1000 person-years, compared with 2.1 events per 1000 person-years for individuals treated with a sulfonylurea. There was no statistically significant reduction in the risk of undergoing joint replacement in people treated with metformin vs a sulfonylurea (aHR, 0.80; 95% CI, 0.50-1.27; P = .34) ( Table 2).     Kaplan-Meier plot in eFigure 5 in Supplement 1. No difference in joint replacement was seen between groups.

Discussion
In this large retrospective cohort study, we found a 24% reduction in the risk of developing OA in individuals with diabetes treated with metformin compared with time-conditional propensity scorematched individuals treated with a sulfonylurea. When stratified by prior exposure to metformin within the sulfonylurea group, the observed benefit associated with metformin compared with sulfonylurea was attenuated in the people treated with a sulfonylurea with prior exposure to metformin compared with those treated with a sulfonylurea with no prior exposure to metformin.
One possible hypothesis for this finding is that individuals in the sulfonylurea group with prior exposure to metformin derived a degree of long-lasting protection associated with the metformin exposure. In a sensitivity analysis comparing individuals only ever treated with metformin with individuals only ever treated with a sulfonylurea, allowing for longer-term follow-up of the outcome (even after stopping the medication of interest), we found a similar 23% reduction in the risk of developing OA in individuals treated with metformin.
This study supports prior literature demonstrating benefit in OA associated with treatment with metformin. 9,11,12 Several preclinical studies have suggested a protective association of metformin in OA through activating AMP-activated protein kinase signaling, decreasing the level of matrix metalloproteinase 13, increasing autophagy and reducing chondrocyte apoptosis, and augmenting chondroprotective and anti-inflammatory properties of mesenchymal stem cells. [9][10][11][12] Human data also support the use of metformin for the treatment or prevention of OA. In an observational study, 8 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. 13 Additional cohort studies have found that individuals with diabetes treated with metformin had a significantly reduced risk of total knee arthroplasty. 14,15 One cohort study found no association between metformin use and incidence of developing OA; however, a systematic review of 10 preclinical and 5 human studies of OA concluded that metformin had chondroprotective, immunomodulatory, and analgesic associations. 26,27 Our study provides further, robust epidemiological evidence that metformin may be associated with protection in the development and progression of OA in individuals with type 2 diabetes.

Strengths and Limitations
Our study has several strengths. We used a large claims database covering individuals in a wide geographic area in the United States. We were able to exclude people with diabetes who were using additional treatments, thus reducing potential confounding from these medications and more effectively isolating the outcomes associated with metformin. We conducted our analysis using a prevalent new-user cohort design with time-conditional propensity score matching, which allowed us to compare persons using metformin users or sulfonylurea at the starting point of each medication, helping to avoid immortal time bias and time-lagging bias. We specifically selected individuals with type 2 diabetes who either required treatment with metformin alone or a sulfonylurea alone to create similar cohorts of people with mild diabetes. We were able to follow up individuals for up to 10 years to ascertain the outcome. We were also able to conduct a sensitivity analysis comparing individuals only ever treated with metformin with those only ever treated with a sulfonylurea, allowing for longer-term follow up for the outcome, which demonstrated similar results as our primary analysis. Our study has several limitations. First, as this is a retrospective study using claims data, there may be residual or unmeasured confounders. To balance the covariates, we used propensity score matching and adjusted for important covariables. Second, we did not have data on body mass index, which is associated with OA. It is possible that metformin use resulted in more weight loss than sulfonylurea use, and the reduction in OA we observed was mediated primarily by weight loss.

JAMA Network Open | Diabetes and Endocrinology
However, studies have shown that weight loss induced by metformin is modest, and a prior randomized clinical trial of diet and exercise that resulted in a similar degree of weight loss did not significantly reduce the risk of developing OA. [28][29][30] We believe metformin likely exerts protective associations beyond what can be attributed to weight loss alone. Third, we also lacked data on level of physical activity or history of trauma to the involved joints, both of which can be associated with OA. However, these factors should not have affected whether patients received metformin or a sulfonylurea for the treatment of diabetes and are thus likely nondifferential between groups.
Fourth, our study only evaluates the association of metformin with the development of OA in patients with diabetes, thus limiting its generalizability. Given the underlying metabolic derangements in patients with diabetes, it is possible that the benefits we observed from metformin treatment would not be seen in patients without diabetes. Fifth, the Optum CDM data set is limited to individuals with commercial or Medicare Advantage coverage, and therefore may not be representative of the entire US population. Sixth, we included people who switched from metformin to sulfonylureas, but not vice versa, to maximize the number of individuals contributing data to the sulfonylurea group, which was substantially smaller in size than the metformin group. This may have created some form of bias; however, we wanted to isolate the associations of metformin alone without potential confounding by prior treatment with a sulfonylurea. Seventh, we used ICD-9, ICD-10, and CPT codes for identification of diseases and outcomes, which could have led to misclassification of variables and outcomes; however, we believe this is likely to be nondifferential between groups. Eighth, we could not determine the degree of medication adherence in the any of the treatment groups.

Conclusions
In our 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.