title: Risk of hypoglycemia following intensification of metformin treatment with insulin versus sulfonylurea.
abstract: BACKGROUND
  Hypoglycemia remains a common life-threatening event associated with diabetes treatment. We compared the risk of first or recurrent hypoglycemia event among metformin initiators who intensified treatment with insulin versus sulfonylurea.
  
  
  METHODS
  We assembled a retrospective cohort using databases of the Veterans Health Administration, Medicare and the National Death Index. Metformin initiators who intensified treatment with insulin or sulfonylurea were followed to either their first or recurrent hypoglycemia event using Cox proportional hazard models. Hypoglycemia was defined as hospital admission or an emergency department visit for hypoglycemia, or an outpatient blood glucose value of less than 3.3 mmol/L. We conducted additional analyses for risk of first hypoglycemia event, with death as the competing risk.
  
  
  RESULTS
  Among 178,341 metformin initiators, 2948 added insulin and 39,990 added sulfonylurea. Propensity score matching yielded 2436 patients taking metformin plus insulin and 12,180 taking metformin plus sulfonylurea. Patients took metformin for a median of 14 (interquartile range [IQR] 5-30) months, and the median glycated hemoglobin level was 8.1% (IQR 7.2%-9.9%) at intensification. In the group who added insulin, 121 first hypoglycemia events occurred, and 466 first events occurred in the group who added sulfonylurea (30.9 v. 24.6 events per 1000 person-years; adjusted hazard ratio [HR] 1.30, 95% confidence interval [CI] 1.06-1.59). For recurrent hypoglycemia, there were 159 events in the insulin group and 585 events in the sulfonylurea group (39.1 v. 30.0 per 1000 person-years; adjusted HR 1.39, 95% CI 1.12-1.72). In separate competing risk analyses, the adjusted HR for hypoglycemia was 1.28 (95% CI 1.04-1.56).
  
  
  CONCLUSIONS
  Among patients using metformin who could use either insulin or sulfonylurea, the addition of insulin was associated with a higher risk of hypoglycemia than the addition of sulfonylurea. This finding should be considered by patients and clinicians when discussing the risks and benefits of adding insulin versus a sulfonylurea.
authors.affiliation: Geriatric Research Education and Clinical Centers (Roumie, Min, Greevy, Grijalva, Hung, Liu, Elasy, Griffin), Veterans Health Administration and Tennessee Valley Healthcare System, Health Services Research and Development Service Centers; Departments of Medicine (Roumie, Min, Hung, Elasy, Griffin), Biostatistics (Greevy, Grijalva, Liu) and Health Policy (Grijalva, Griffin), Vanderbilt University, Nashville, Tenn. christianne.roumie@vanderbilt.edu.
authors.forename: Christianne L
authors.initials: CL
authors.lastname: Roumie
authors.affiliation: Geriatric Research Education and Clinical Centers (Roumie, Min, Greevy, Grijalva, Hung, Liu, Elasy, Griffin), Veterans Health Administration and Tennessee Valley Healthcare System, Health Services Research and Development Service Centers; Departments of Medicine (Roumie, Min, Hung, Elasy, Griffin), Biostatistics (Greevy, Grijalva, Liu) and Health Policy (Grijalva, Griffin), Vanderbilt University, Nashville, Tenn.
authors.forename: Jea Young
authors.initials: JY
authors.lastname: Min
authors.affiliation: Geriatric Research Education and Clinical Centers (Roumie, Min, Greevy, Grijalva, Hung, Liu, Elasy, Griffin), Veterans Health Administration and Tennessee Valley Healthcare System, Health Services Research and Development Service Centers; Departments of Medicine (Roumie, Min, Hung, Elasy, Griffin), Biostatistics (Greevy, Grijalva, Liu) and Health Policy (Grijalva, Griffin), Vanderbilt University, Nashville, Tenn.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Greevy
authors.affiliation: Geriatric Research Education and Clinical Centers (Roumie, Min, Greevy, Grijalva, Hung, Liu, Elasy, Griffin), Veterans Health Administration and Tennessee Valley Healthcare System, Health Services Research and Development Service Centers; Departments of Medicine (Roumie, Min, Hung, Elasy, Griffin), Biostatistics (Greevy, Grijalva, Liu) and Health Policy (Grijalva, Griffin), Vanderbilt University, Nashville, Tenn.
authors.forename: Carlos G
authors.initials: CG
authors.lastname: Grijalva
authors.affiliation: Geriatric Research Education and Clinical Centers (Roumie, Min, Greevy, Grijalva, Hung, Liu, Elasy, Griffin), Veterans Health Administration and Tennessee Valley Healthcare System, Health Services Research and Development Service Centers; Departments of Medicine (Roumie, Min, Hung, Elasy, Griffin), Biostatistics (Greevy, Grijalva, Liu) and Health Policy (Grijalva, Griffin), Vanderbilt University, Nashville, Tenn.
authors.forename: Adriana M
authors.initials: AM
authors.lastname: Hung
authors.affiliation: Geriatric Research Education and Clinical Centers (Roumie, Min, Greevy, Grijalva, Hung, Liu, Elasy, Griffin), Veterans Health Administration and Tennessee Valley Healthcare System, Health Services Research and Development Service Centers; Departments of Medicine (Roumie, Min, Hung, Elasy, Griffin), Biostatistics (Greevy, Grijalva, Liu) and Health Policy (Grijalva, Griffin), Vanderbilt University, Nashville, Tenn.
authors.forename: Xulei
authors.initials: X
authors.lastname: Liu
authors.affiliation: Geriatric Research Education and Clinical Centers (Roumie, Min, Greevy, Grijalva, Hung, Liu, Elasy, Griffin), Veterans Health Administration and Tennessee Valley Healthcare System, Health Services Research and Development Service Centers; Departments of Medicine (Roumie, Min, Hung, Elasy, Griffin), Biostatistics (Greevy, Grijalva, Liu) and Health Policy (Grijalva, Griffin), Vanderbilt University, Nashville, Tenn.
authors.forename: Tom
authors.initials: T
authors.lastname: Elasy
authors.affiliation: Geriatric Research Education and Clinical Centers (Roumie, Min, Greevy, Grijalva, Hung, Liu, Elasy, Griffin), Veterans Health Administration and Tennessee Valley Healthcare System, Health Services Research and Development Service Centers; Departments of Medicine (Roumie, Min, Hung, Elasy, Griffin), Biostatistics (Greevy, Grijalva, Liu) and Health Policy (Grijalva, Griffin), Vanderbilt University, Nashville, Tenn.
authors.forename: Marie R
authors.initials: MR
authors.lastname: Griffin
mesh_terms: D000368:Aged; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced / Q000453:epidemiology*; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects; D015994:Incidence; D007328:Insulin / Q000008:administration & dosage / Q000009:adverse effects*; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000009:adverse effects*; D008875:Middle Aged; D057216:Propensity Score; D012189:Retrospective Studies; D013453:Sulfonylurea Compounds / Q000008:administration & dosage / Q000009:adverse effects*; D015996:Survival Rate / Q000639:trends; D013714:Tennessee / Q000453:epidemiology
chemical_list: D001786:Blood Glucose; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D008687:Metformin; D013453:Sulfonylurea Compounds
references.citation: Diabetes Care. 2015 Feb;38(2):316-22
references.pmid: 25492401
references.citation: Diabetes Care. 2007 Feb;30(2):389-94
references.pmid: 17259518
references.citation: Clin J Am Soc Nephrol. 2009 Jun;4(6):1121-7
references.pmid: 19423569
references.citation: Clin Pharmacol Ther. 2011 Dec;90(6):813-9
references.pmid: 22048232
references.citation: Ann Intern Med. 2012 Nov 6;157(9):601-10
references.pmid: 23128859
references.citation: Med Care. 2007 Mar;45(3):214-23
references.pmid: 17304078
references.citation: Diabetes Care. 2012 Sep;35(9):1897-901
references.pmid: 22699297
references.citation: BMJ. 2013;347:f4533
references.pmid: 23900314
references.citation: Diabetes Care. 2011 May;34(5):1164-70
references.pmid: 21421802
references.citation: Diabetes Care. 2014 Apr;37(4):1024-31
references.pmid: 24513587
references.citation: Am J Epidemiol. 2003 Nov 1;158(9):915-20
references.pmid: 14585769
references.citation: Can J Diabetes. 2013 Apr;37 Suppl 1:S1-3
references.pmid: 24070926
references.citation: Am J Kidney Dis. 2012 Nov;60(5):850-86
references.pmid: 23067652
references.citation: BMJ. 2010;340:b4909
references.pmid: 20061358
references.citation: J Clin Epidemiol. 1994 Jul;47(7):731-7
references.pmid: 7722586
references.citation: BMC Endocr Disord. 2008 Apr 01;8:4
references.pmid: 18380903
references.citation: Am J Epidemiol. 2009 Apr 15;169(8):1033-8
references.pmid: 19251753
references.citation: Kidney Int. 2012 Apr;81(7):698-706
references.pmid: 22258320
references.citation: Lancet. 1998 Sep 12;352(9131):837-53
references.pmid: 9742976
references.citation: N Engl J Med. 2008 Jun 12;358(24):2545-59
references.pmid: 18539917
references.citation: JAMA. 1997 Jul 2;278(1):40-3
references.pmid: 9207336
references.citation: Arch Intern Med. 1997 Aug 11-25;157(15):1681-6
references.pmid: 9250229
references.citation: Ann Intern Med. 2007 Dec 4;147(11):755-65
references.pmid: 18056659
references.citation: J Diabetes Complications. 2011 Nov-Dec;25(6):355-61
references.pmid: 22055259
references.citation: Medicare Medicaid Res Rev. 2012;2(3). pii: mmrr.002.03.a06. doi: 10.5600/mmrr.002.03.a06
references.pmid: 24800148
references.citation: BMC Endocr Disord. 2012 May 30;12:5
references.pmid: 22646230
references.citation: JAMA. 2014 Jun 11;311(22):2288-96
references.pmid: 24915260
references.citation: Am J Epidemiol. 2015 Apr 1;181(7):532-40
references.pmid: 25693770
references.citation: Diabetes Care. 2015 Jan;38 Suppl:S4
references.pmid: 25537706
references.citation: JAMA Intern Med. 2014 Jul;174(7):1116-24
references.pmid: 24838229
references.citation: Diabetes Educ. 2008 Jul-Aug;34(4):683-91
references.pmid: 18669810
references.citation: JAMA Intern Med. 2014 Aug;174(8):1227-34
references.pmid: 24979148
references.citation: JAMA. 2014 Jun 25;311(24):2518-31
references.pmid: 24892770
references.citation: Diabetes Care. 2012 Dec;35(12):2650-64
references.pmid: 23100048
references.citation: N Engl J Med. 2010 Oct 7;363(15):1410-8
references.pmid: 20925543
references.citation: N Engl J Med. 2011 Nov 24;365(21):2002-12
references.pmid: 22111719