title: Metformin in combination with various insulin secretagogues in type 2 diabetes and associated risk of cardiovascular morbidity and mortality--a retrospective nationwide study.
abstract: OBJECTIVE
  Metformin is the first-line treatment for most patients with type 2 diabetes but many patients need additional treatment with insulin secretagogues (IS) to achieve glycemic control. We aimed to compare mortality and cardiovascular risk among users of metformin in combination with pharmacologically different ISs.
  
  
  METHODS
  Using nationwide administrative Danish registries, we followed all individuals without prior stroke or myocardial infarction who initiated metformin and an IS from 1997 through 2009. Rate ratios (RR) of all-cause mortality, cardiovascular death, and a composite of myocardial infarction, stroke, or cardiovascular death were compared between user groups using time-dependent multivariable Poisson regression models. The most common combination, glimepiride+metformin, was used as reference.
  
  
  RESULTS
  A total of 56,827 patients were included, 56% male, the mean age was 61 ± 12.5 years, and median duration of prior monotherapy was 2.2 (inter quartile range 0.5-4.5) years. Crude incidence rates of mortality for combinations of ISs with metformin were; 15.4 (repaglinide), 28.1 (glipizide), 23.7 (glibenclamide), 21.1 (gliclazide), 20.7 (glimepiride), 27.7 (tolbutamide) deaths per 1000 person years. In adjusted analysis, the associated mortality risk was similar for users of gliclazide+metformin (RR=1.01 [0.88-1.15]), repaglinide+metformin (RR=0.81 [0.62-1.05]), glibenclamide+metformin (RR=0.98 [0.87-1.10]), and tolbutamide+metformin (RR=1.04 [0.85-1.28]). Users of glipizide+metformin was associated with increased all-cause mortality (RR=1.16 [1.02-1.32], p=0.02), cardiovascular death (RR=1.21 [1.01-1.46], p=0.04), and the combined endpoint (RR=1.20 [1.06-1.36, p=0.005).
  
  
  CONCLUSIONS
  Most ISs in combination with metformin were associated with similar mortality and cardiovascular risk. Whether glipizide is associated with increased risk compared with other ISs when used in combinations with metformin warrants further study.
authors.affiliation: Department of Cardiology, University Hospital Rigshospitalet, Copenhagen, Denmark. Electronic address: ulrik_mogensen@hotmail.com.
authors.forename: Ulrik Madvig
authors.initials: UM
authors.lastname: Mogensen
authors.affiliation: Department of Cardiology, University Hospital Gentofte, Copenhagen, Denmark.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Andersson
authors.affiliation: Department of Cardiology, University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: Emil Loldrup
authors.initials: EL
authors.lastname: Fosbøl
authors.affiliation: Department of Cardiology, University Hospital Frederiksberg, Copenhagen, Denmark.
authors.forename: Tina Ken
authors.initials: TK
authors.lastname: Schramm
authors.affiliation: Department of Endocrinology, University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: Allan
authors.initials: A
authors.lastname: Vaag
authors.affiliation: Department of Health Science and Technology, Aalborg University, Aalborg, Denmark.
authors.forename: Nikolai Madrid
authors.initials: NM
authors.lastname: Scheller
authors.affiliation: Department of Health Science and Technology, Aalborg University, Aalborg, Denmark.
authors.forename: Christian
authors.initials: C
authors.lastname: Torp-Pedersen
authors.affiliation: Department of Cardiology, University Hospital Gentofte, Copenhagen, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; National Institute of Public Health, University of Southern Denmark, Odense, Denmark.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Gislason
authors.affiliation: Department of Cardiology, University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Køber
mesh_terms: D000368:Aged; D002219:Carbamates / Q000008:administration & dosage; D002318:Cardiovascular Diseases / Q000453:epidemiology* / Q000401:mortality; D003718:Denmark / Q000453:epidemiology; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000453:epidemiology*; D004359:Drug Therapy, Combination; D005260:Female; D005907:Gliclazide / Q000008:administration & dosage; D005913:Glipizide / Q000008:administration & dosage; D005905:Glyburide / Q000008:administration & dosage; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D008297:Male; D008687:Metformin / Q000008:administration & dosage*; D008875:Middle Aged; D009017:Morbidity; D009203:Myocardial Infarction / Q000401:mortality; D010880:Piperidines / Q000008:administration & dosage; D012042:Registries / Q000706:statistics & numerical data; D012189:Retrospective Studies; D012307:Risk Factors; D020521:Stroke / Q000401:mortality; D013453:Sulfonylurea Compounds / Q000008:administration & dosage; D014044:Tolbutamide / Q000008:administration & dosage
chemical_list: D002219:Carbamates; C417231:Glucovance; D007004:Hypoglycemic Agents; D010880:Piperidines; D013453:Sulfonylurea Compounds; C072379:repaglinide; C057619:glimepiride; D008687:Metformin; D014044:Tolbutamide; D005907:Gliclazide; D005905:Glyburide; D005913:Glipizide
keywords: Cardiovascular risk; Combination therapy; Insulin secretagogues; Metformin; Sulfonylurea; Type 2 diabetes