The management of diabetes mellitus in patients with chronic kidney disease: a population-based study in Southern Italy Clinical Drug Investigation Gianluca Trifirò1, Fabrizio Parrino1, Valeria Pizzimenti1, Francesco Giorgianni1, Janet Sultana1, Marco Muscianisi1, Chiara Troncone2, Daniele UgoTari2, Vincenzo Arcoraci1, Domenico Santoro1, Giusi Russo1, Viviana Lacava 1, Achille P. Caputi1 1Department of Clinical and Experimental Medicine, Pharmacology Section, University of Messina, Italy; 2 Caserta - Local Health Service, Caserta, Italy Corresponding author: Gianluca Trifirò, MD, PhD Assistant Professor of Pharmacology, Department of Clinical and Experimental Medicine, Policlinico Universitario G. Martino, Via Consolare Valeria, Messina 98125, Italy e-mail: trifirog@unime.it tel. +39 0902213264 fax +39 0902213300 Online Resource 1: Anti-diabetic drugs classified as “not contraindicated in CKD”, “contraindicated” or “requiring dose adjustment” based on clearance information. Abbreviations- CKD: chronic kidney disease Not contraindicated in CKD Contraindicated in CKD (creatinine clearance between 30-90 ml/min) Contraindicated in CKD (creatinine clearance < 30 ml/min) Contraindicated in CKD (without information on creatinine clearance) Drugs requiring dose adjustment Glipizide Chlorpropamide Glimepiride and pioglitazone combination therapy Glibenclamide Insulins Glicazide Rosiglitazone and metformin combination therapy Acarbose Gliquidone Sitagliptin Glimepiride Pioglitazone and metformin combination therapy Exenatide Phenformin and sulphonamide combination therapy Vildagliptin Rosiglitazone Metformin and vildagliptin combination therapy Liraglutide Metformin and sulphonamides combination therapy Saxagliptin Pioglitazone Metformin and sitagliptin combination therapy - - - - - - - - Repaglinide Linagliptin Metformin - Online Resource 2: Time to discontinuation of specific anti-diabetic therapy during the first year following a new CKD diagnosis, stratified by drug class. Abbreviations- CKD: chronic kidney disease. Other anti-diabetic drugs were excluded from this analysis due to limited number of patients who were Survival treated with these drugs (n=4). Days since new CKD diagnosis Online Resource 3: Number of CKD patients with diabetes (DKD) or without diabetes mellitus stratified by stage of kidney disease. Abbreviations- CKD: chronic kidney disease; DKD: diabetic kidney disease; DM: diabetes mellitus CKD Stage CKD patients without DM DKD patients Overall N/A 925 558 1,483 <3 103 46 149 ≥3 166 83 249 Online Resource 4: Prevalence of anti-diabetic drug use per 100 inhabitants, stratified by time period and type of contraindication; this analysis was restricted to patients with advanced stages of CKD (≥ stage 3). No patients were prescribed anti-diabetic drugs contraindicated in creatinine clearance <30ml/min. The error bars represent the 95% confidence intervals. Statistical significance is denoted by non-overlapping error bars of the first and second column Abbreviation- ID: index date; CKD: Prevalence of anti-diabetic drug use per 100 inhabitants (%) chronic kidney disease. 70 One year prior to ID One year after ID 60 50 40 30 20 10 0 Contraindicated in CKD Contraindicated in CKD Drugs requiring dose (without information on (creatinine clearance adjustment creatinine clearance) between 30-90 ml/min) Not contraindicated in CKD