title: Sulphonylurea compared to DPP-4 inhibitors in combination with metformin carries increased risk of severe hypoglycemia, cardiovascular events, and all-cause mortality.
abstract: OBJECTIVE
  There are safety concerns related to sulphonylurea treatment. The objective of this nationwide study was to compare the risk of cardiovascular disease (CVD), all-cause mortality and severe hypoglycemia in patients with type 2 diabetes (T2D) starting second-line treatment with either metformin+sulphonylurea or metformin+dipeptidyl peptidase-4 inhibitor (DPP-4i).
  
  
  METHODS
  All patients with T2D in Sweden who initiated second-line treatment with metformin+sulphonylurea or metformin+DPP-4i during 2006-2013 (n=40,736 and 12,024, respectively) were identified in this nationwide study. The Swedish Prescribed Drug Register and the Cause of Death and National Patient Registers were used, and Cox survival models adjusted for age, sex, fragility, prior CVD, and CVD-preventing drugs were applied to estimate risks of events. Propensity score adjustments and matching methods were used to test the results.
  
  
  RESULTS
  Of 52,760 patients; 77% started metformin+SU and 23% metformin+DPP-4i. Crude incidences for severe hypoglycemia, CVD, and all-cause mortality in the SU cohort were 2.0, 19.6, and 24.6 per 1000 patient-years and in the DPP-4i cohort were 0.8, 7.6, and 14.9 per 1000 patient-years, respectively. Sulphonylurea compared with DPP4i was associated with higher risk of subsequent severe hypoglycemia, fatal and nonfatal CVD, and all-cause mortality; adjusted HR (95% CI): 2.07 (1.11-3.86); 1.17 (1.01-1.37); and 1.25 (1.02-1.54), respectively. Results were confirmed by additional propensity-adjusted and matched analyses. Among the SU drugs, glibenclamide had the highest risks.
  
  
  CONCLUSIONS
  Metformin+SU treatment was associated with an increased risk of subsequent severe hypoglycemia, cardiovascular events, and all-cause mortality compared with metformin+DPP4i. Results from randomized trials will be important to elucidate causal relationships.
authors.affiliation: Department of Medical Sciences, Clinical Diabetes and Metabolism, Uppsala University, Uppsala, Sweden.
authors.forename: Jan W
authors.initials: JW
authors.lastname: Eriksson
authors.affiliation: AstraZeneca Nordic-Baltic, Södertälje, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Bodegard
authors.affiliation: Department of Clinical Science and Education, Division of Internal Medicine, Unit for Diabetes Research, Karolinska Institute, Södersjukhuset, Stockholm, Sweden.
authors.forename: David
authors.initials: D
authors.lastname: Nathanson
authors.affiliation: Statisticon AB, Uppsala, Sweden.
authors.forename: Marcus
authors.initials: M
authors.lastname: Thuresson
authors.affiliation: Department of Clinical Science and Education, Division of Internal Medicine, Unit for Diabetes Research, Karolinska Institute, Södersjukhuset, Stockholm, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Nyström
authors.affiliation: Cardiology Unit, Department of Medicine, Solna, Karolinska Institute, Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Norhammar
mesh_terms: D000368:Aged; D001786:Blood Glucose / Q000032:analysis; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000401:mortality; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000009:adverse effects*; D004359:Drug Therapy, Combination; D005260:Female; D005905:Glyburide / Q000627:therapeutic use; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced / Q000401:mortality*; D007004:Hypoglycemic Agents / Q000009:adverse effects; D015994:Incidence; D008297:Male; D008687:Metformin / Q000009:adverse effects*; D008875:Middle Aged; D009203:Myocardial Infarction / Q000139:chemically induced / Q000401:mortality*; D016016:Proportional Hazards Models; D012307:Risk Factors; D013453:Sulfonylurea Compounds / Q000009:adverse effects*; D013548:Sweden / Q000453:epidemiology
chemical_list: D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D005905:Glyburide; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D008687:Metformin; D013453:Sulfonylurea Compounds; C517652:hemoglobin A1c protein, human
keywords: All-cause mortality; Cardiovascular disease; DPP-4i; Epidemiology; Hypoglycemia; Sulfonylurea