title: Cardiovascular safety of metformin and sulfonylureas in patients with different cardiac risk profiles.
abstract: Based on previous experiences, the Food and Drug Administration and the European Medicines Agency recommend that clinical trials for novel antidiabetic drugs are powered to detect increased cardiovascular risk. In this context, data concerning licensed drugs such as metformin and sulfonylureas are conflicting. The influence of baseline cardiovascular risk on any treatment effect appears obvious but has not been formally proven. We therefore evaluated association of metformin and sulfonylureas with cardiovascular events in patients with different cardiovascular risk profiles indicated by N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) levels.
  
  
  
  2024 patients with diabetes mellitus were included in this observational study. The primary endpoint was defined as a combination of cardiovascular events and death. Association of metformin and sulfonylureas was assessed using Cox regression models. Possible differences of these associations in patients with different NT-proBNP levels were studied by stratifying and through interaction analysis.
  
  
  
  During a median follow-up of 60 months, the primary endpoint occurred in 522 (26%) of patients. The median age was 63 years. A Cox regression analysis was adjusted for site of treatment, concomitant medication, age, gender, body mass index, glycated haemoglobin, duration of diabetes, glomerular filtration rate, cholesterol, and history of smoking and cardiac disease. Metformin was associated with a decreased risk in the cohort with elevated NT-proBNP ≥300 pg/mL (HR 0.70, p=0.014) and a similar association was found for the interaction between metformin and NT-proBNP (p=0.001). There was neither an association for sulfonylureas nor a significant interaction between sulfonylureas and NT-proBNP.
  
  
  
  Metformin is associated with beneficial cardiovascular outcomes in patients with diabetes only when (sub)clinical cardiovascular risk defined by NT-proBNP levels is present.
authors.affiliation: Department of Cardiology, Medical University of Vienna, Vienna, Austria.
authors.forename: Raphael
authors.identifier: 0000-0003-3027-7775
authors.initials: R
authors.lastname: Wurm
authors.affiliation: Department of Endocrinology, Medical University of Vienna, Vienna, Austria Department of Internal Medicine, Barmherzige Brüder, Linz, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Resl
authors.affiliation: Division of Cardiothoracic and Vascular Anaesthesia and Intensive Care, Department of Anaesthesia, General Intensive Care and Pain Control, Medical University of Vienna, Vienna, Austria.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Neuhold
authors.affiliation: Karl Landsteiner Institute for Nephrology and Diabetes, Hietzing Hospital Vienna, Vienna, Austria.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Prager
authors.affiliation: Diabetes Outpatient Clinic, Health Center South, Vienna, Austria.
authors.forename: Helmut
authors.initials: H
authors.lastname: Brath
authors.affiliation: Diabetes Outpatient Clinic, Health Center Strohgasse, Vienna, Austria.
authors.forename: Claudia
authors.initials: C
authors.lastname: Francesconi
authors.affiliation: Department of Endocrinology, Medical University of Vienna, Vienna, Austria.
authors.forename: Greisa
authors.initials: G
authors.lastname: Vila
authors.affiliation: Complexity-Research, Research Institute for Complex Systems, Vienna, Austria.
authors.forename: Guido
authors.initials: G
authors.lastname: Strunk
authors.affiliation: Department of Internal Medicine, Barmherzige Brüder, Linz, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Clodi
authors.affiliation: Department of Endocrinology, Medical University of Vienna, Vienna, Austria.
authors.forename: Anton
authors.initials: A
authors.lastname: Luger
authors.affiliation: Department of Cardiology, Medical University of Vienna, Vienna, Austria.
authors.forename: Richard
authors.initials: R
authors.lastname: Pacher
authors.affiliation: Department of Cardiology, Medical University of Vienna, Vienna, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Hülsmann
mesh_terms: D000368:Aged; D001317:Austria; D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000097:blood / Q000175:diagnosis / Q000209:etiology / Q000517:prevention & control*; D016009:Chi-Square Distribution; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008687:Metformin / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000097:blood; D010446:Peptide Fragments / Q000097:blood; D016016:Proportional Hazards Models; D011446:Prospective Studies; D065840:Protective Factors; D018570:Risk Assessment; D012307:Risk Factors; D013453:Sulfonylurea Compounds / Q000009:adverse effects / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D007004:Hypoglycemic Agents; D010446:Peptide Fragments; D013453:Sulfonylurea Compounds; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain; D008687:Metformin