1. Severity of Diabetes Mellitus and Risk of Total Hip or Knee Replacement: a Population Based Case-Control Study Methods We performed a population based case-control study using the Clinical Practice Research Datalink (CPRD). Cases (n=94,609) were defined as patients ≥18 years who had undergone TJR between 2000 and 2012. Controls were matched by age, gender and general practice. Conditional logistic regression was used to estimate the risk of total knee (TKR) and total hip replacement (THR) surgery associated with use of antidiabetic drugs (AD). We additionally stratified current AD users by proxies for OA severity. Conclusions This study does not support the theory that DM patients are more likely to suffer from severe OA as compared to patients without diabetes. Moreover, risk of severe OA necessitating TJR decreases with increasing DM severity. This is possibly due to dissimilarities in methodology, a decrease in eligibility for surgery, or variability of OA phenotypes. Corresponding author Frank de Vries frank.de.vries@mumc.nl Maastricht UMC+ Department of Clinical Pharmacy & Toxicology P.O. Box 5800 6202 AZ Maastricht, The Netherlands Department of Epidemiology Introduction Patients with Diabetes Mellitus (DM) are more likely to suffer from osteoarthritis (OA). DM is characterized by several metabolic problems, such as impaired glucose metabolism and obesity. It is generally thought that people with DM are more likely to suffer from OA due to an increased Body Mass Index (BMI), resulting in the mechanical destruction of cartilage. However, previous studies have suggested a coexisting metabolic causality (Figure 1). Objective To evaluate the risk of hip or knee replacement, as a proxy for severe OA, in patients with DM. We additionally evaluated the risk of total joint replacement (TJR) with various proxies for increased DM severity. Table 1 Baseline characteristics TKR patients n=89,536 (%) THR patients n=99,682 (%) CharacteristicCases n=44,768 Controls n=44,768 Cases n=49,841 Controls n=49,841 Mean age (SD) 69.5 (9.5) 68.8 (11.5) Female 24,912 (55.6) 29,724 (59.6) Mean BMI (SD) 29.7 (5.2)27.0 (5.1)27.6 (5.0)26.8 (5.0) Mean HbA1c (% (SD)) 6.9 (1.2)7.1 (1.4)6.8 (1.2)7.2 (1.4) History of DM diagnosis DM regardless of type 5,118 (11.4)4,325 (10.3)4,075 (8.2)4,591 (9.2) Type I 149 (0.3)211 (0.5)189 (0.4)243 (0.5) Type II 4,636 (10.4)4,077 (9.1)3,579 (7.2)3,979 (8.0) Type unspecified 333 (0.7)307 (0.7)307 (0.6)369 (0.7) TKR= Total Knee Replacement, THR = Total Hip replacement, SD= Standard Deviation, BMI = Body Mass Index Figure 1. Flowchart linking DM and osteoarthritis. DM = Diabetes Mellitus; AGEs = advanced glycation end products. DM Blood glucose Blood AGEs Cartilage damage Cartilage repair Osteoarthritis Results Current AD use was significantly associated with a lower risk of TKR (OR=0.86 (95% CI=0.78-0.94)) and THR (OR=0.90 (95% CI=0.82-0.99)) compared to patients not using ADs. Moreover, risk of TKR and THR was decreased with increasing HbA1c (Table 2). TKR n= (89,536) THR n= (99,682) AD useCasesControlsCrude OR (95% CI)Adjusted OR (95% CI) a CaseControlCrude OR (95% CI)Adjusted OR (95% CI) b Never 4089641237ref 4685346304ref Past 1761790.99 (0.81-1.22)0.96 (0.75-1.24) 1661690.96 (0.78-1.20)0.97 (0.76-1.25) Recent 731000.74 (0.54-1.00)0.74 (0.51-1.07) 74960.76 (0.56-1.04)0.84 (0.59-1.19) Current 362332521.12 (1.07-1.18)0.86 (0.78-0.94) 274832720.83 (0.79-0.87)0.90 (0.81-0.99) By HbA1c, most recent in year prior to index date <6.5% 7185011.45 (1.29-1.63)0.93 (0.81-1.07) 5945231.12 (0.99-1.26)1.05 (0.92-1.21) 6.5-7.9% 177114891.20 (1.12-1.29)0.87 (0.79-0.95) 120514010.85 (0.78-0.92)0.88 (0.80-0.97) 8-9.4% 5125470.94 (0.83-1.07)0.67 (0.58-0.78) 3825100.74 (0.65-0.84)0.73 (0.63-0.86) >9.5% 1762800.63 (0.52-0.76)0.53 (0.42-0.66) 1232930.41 (0.33-0.51)0.44 (0.34-0.56) HbA1c missing 4464351.03 (0.90-1.18)0.75 (0.64-0.88) 4445450.80 (0.71-0.91)0.81 (0.70-0.94) TKR = Total Knee Replacement, THR = Total Hip Replacement, AD = Antidiabetic Drug, OR = Odds Ratio, CI = Confidence Interval, BMI = Body Mass Index, a) Adjusted for: Smoking status and BMI. Drug use in previous 6 months: statins, thiazides, calcium channel blockers, beta-blockers, RAAS inhibitors, loop diuretics, non-selective NSAIDs, COX2- selective NSAIDs. History of comorbidity ever before: acute myocardial infarction, heart failure, cerebrovascular events, peripheral vascular disorders, ulcers. Retinopathy or neuropathy in 5 years prior to TKR. Most recent value in previous year for HbA1c and fasting glucose. Stratified variables were excluded as confounder in the analyses stratified by that variable. b) Adjusted for: Smoking status and BMI. Drug use in previous 6 months: statins, thiazides, calcium channel blockers, beta-blockers, RAAS inhibitors, loop diuretics, non-selective NSAIDs, COX2- selective NSAIDs. Retinopathy in 5 years prior to THR. Most recent value in previous year for HbA1c and fasting glucose. Stratified variables were excluded as confounder in the analyses stratified by that variable. Table 2 Risk of TKR and THR in current AD users compared with controls, stratified by HbA1c Yannick Nielen (1,2), Bart van den Bemt (3,4), Annelies Boonen (5), Pieter C. Dagnelie (2), Pieter Emans (6), Arief Lalmohamed (7), Anthonius de Boer (1), Frank de Vries (1,8) 1 Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht University, Utrecht, the Netherlands. 2 Department of Epidemiology, Maastricht University, the Netherlands. 3 Department of Pharmacy, Sint Maartenskliniek, Nijmegen, Netherlands. 4 Department of Pharmacy, Radboud University Medical Center, Nijmegen, the Netherlands. 5 Department of Rheumatology, Maastricht University Medical Center+, Maastricht, the Netherlands. 6 Department of Orthopaedics, Maastricht University Medical Center+, Maastricht, the Netherlands. 7 Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht, the Netherlands. 8 Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Center+, Maastricht, the Netherlands Conflict of Interest Mr. Nielen, Dr, Dagnelie, Dr. Lalmohammed, Dr. de Boer, and Dr. de Vries have nothing to disclose; Dr. van den Bemt reports grants and personal fees from Pfizer, grants and personal fees from Roche, personal fees from Abbvie, personal fees from MSD, outside the submitted work; Dr. Boonen reports grants from Abbvie, grants from Pfizer, grants from Merck, personal fees from UCB, personal fees from Sandoz, grants from Amgen, outside the submitted work; Dr. Emans reports grants from Stryker, grants from Active implants, grants from Carbylan Biosurgery, grants from DSM Biomedical, grants from Regentis, personal fees from Biomet, personal fees from Push braces, outside the submitted work.