title: Systematic review: comparative effectiveness and safety of premixed insulin analogues in type 2 diabetes.
abstract: BACKGROUND
  Evidence comparing premixed insulin analogues (a mixture of rapid-acting and intermediate-acting insulin analogues) with other antidiabetic agents is urgently required to guide appropriate therapy.
  
  
  OBJECTIVE
  To summarize the English-language literature on the effectiveness and safety of premixed insulin analogues compared with other antidiabetic agents in adults with type 2 diabetes.
  
  
  METHODS
  The authors searched MEDLINE, EMBASE, CINAHL, and the Cochrane Central Register of Controlled Trials from inception to February 2008 and sought unpublished data from the U.S. Food and Drug Administration, European Medicines Agency, and industry.
  
  
  METHODS
  Studies with control groups that compared premixed insulin analogues with another antidiabetic medication in adults with type 2 diabetes.
  
  
  METHODS
  2 reviewers using standardized protocols performed serial abstraction.
  
  
  RESULTS
  Evidence from clinical trials was inconclusive for clinical outcomes, such as mortality. Therefore, the review focused on intermediate outcomes. Premixed insulin analogues were similar to premixed human insulin in decreasing fasting glucose levels, hemoglobin A(1c) levels, and the incidence of hypoglycemia but were more effective in decreasing postprandial glucose levels (mean difference, -1.1 mmol/L; 95% CI, -1.4 to -0.7 mmol/L [-19.2 mg/dL; 95% CI, -25.9 to -12.5 mg/dL]). Compared with long-acting insulin analogues, premixed insulin analogues were superior in decreasing postprandial glucose levels (mean difference, -1.5 mmol/L; CI, -1.9 to -1.2 mmol/L [-27.9 mg/dL; CI, -34.3 to -21.5 mg/dL]) and hemoglobin A(1c) levels (mean difference, -0.39% [CI, -0.50% to -0.28%]) but were inferior in decreasing fasting glucose levels (mean difference, 0.7 mmol/L; CI, 0.3 to 1.0 mmol/L [12.0 mg/dL; CI, 6.0 to 18.1 mg/dL]) and were associated with a higher incidence of hypoglycemia. Compared with noninsulin antidiabetic agents, premixed insulin analogues were more effective in decreasing fasting glucose levels (mean difference, -1.1 mmol/L; CI, -1.7 to -0.6 mmol/L [-20.5 mg/dL; CI, -29.9 to -11.2 mg/dL]), postprandial glucose levels (mean difference, -2.1 mmol/L; CI, -3.4 to -0.8 mmol/L [-37.4 mg/dL; CI, -61.0 to -13.7 mg/dL]), and hemoglobin A(1c) levels (mean difference, -0.49% [CI, -0.86% to -0.12%]) but were associated with a higher incidence of hypoglycemia.
  
  
  CONCLUSIONS
  The literature search was restricted to studies published in English. Data on clinical outcomes were limited. The small number of studies for each comparison limited assessment of between-study heterogeneity.
  
  
  CONCLUSIONS
  Premixed insulin analogues provide glycemic control similar to that of premixed human insulin and may provide tighter glycemic control than long-acting insulin analogues and noninsulin antidiabetic agents.
authors.affiliation: Evidence-based Practice Center, Johns Hopkins University, Baltimore, Maryland, USA. rqayyum@jhmi.edu
authors.forename: Rehan
authors.initials: R
authors.lastname: Qayyum
authors.forename: Shari
authors.initials: S
authors.lastname: Bolen
authors.forename: Nisa
authors.initials: N
authors.lastname: Maruthur
authors.forename: Leonard
authors.initials: L
authors.lastname: Feldman
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Wilson
authors.forename: Spyridon S
authors.initials: SS
authors.lastname: Marinopoulos
authors.forename: Padmini
authors.initials: P
authors.lastname: Ranasinghe
authors.forename: Muhammed
authors.initials: M
authors.lastname: Amer
authors.forename: Eric B
authors.initials: EB
authors.lastname: Bass
mesh_terms: D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004339:Drug Compounding; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D007328:Insulin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D008297:Male
chemical_list: D001786:Blood Glucose; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin
references.citation: Acta Diabetol. 2003 Dec;40(4):187-92
references.pmid: 14740279
references.citation: Diabetologia. 2007 Feb;50(2):259-67
references.pmid: 17160407
references.citation: Clin Ther. 2004 Apr;26(4):531-40
references.pmid: 15189750
references.citation: Diabetes Obes Metab. 2007 Sep;9(5):724-32
references.pmid: 17593237
references.citation: Diabetes Care. 2008 Jan;31 Suppl 1:S12-54
references.pmid: 18165335
references.citation: Diabetes Care. 2005 Feb;28(2):260-5
references.pmid: 15677776
references.citation: Diabet Med. 2006 Jul;23(7):743-9
references.pmid: 16842478
references.citation: Diabetes Obes Metab. 2009 Jan;11(1):27-32
references.pmid: 17941873
references.citation: J Natl Cancer Inst. 1959 Apr;22(4):719-48
references.pmid: 13655060
references.citation: Horm Metab Res. 2004 Mar;36(3):188-93
references.pmid: 15057674
references.citation: Diabetes Care. 2008 Jan;31(1):20-5
references.pmid: 17934150
references.citation: Clin Ther. 2002 Jan;24(1):73-86
references.pmid: 11833837
references.citation: Clin Ther. 2004 Dec;26(12):2034-44
references.pmid: 15823767
references.citation: Diabetes Res Clin Pract. 2008 Jan;79(1):171-6
references.pmid: 17919762
references.citation: Clin Ther. 2001 Oct;23(10):1732-44
references.pmid: 11726007
references.citation: Diabetes Care. 2008 Jun;31(6):1132-7
references.pmid: 18339972
references.citation: Endocr Pract. 2006 Jan-Feb;12 Suppl 1:42-6
references.pmid: 16627379
references.citation: Clin Ther. 2007 Nov;29(11):2374-84
references.pmid: 18158078
references.citation: Biometrics. 1994 Dec;50(4):1088-101
references.pmid: 7786990
references.citation: Control Clin Trials. 1996 Feb;17(1):1-12
references.pmid: 8721797
references.citation: Lancet. 1998 Sep 12;352(9131):837-53
references.pmid: 9742976
references.citation: Prog Cardiovasc Dis. 1985 Mar-Apr;27(5):335-71
references.pmid: 2858114
references.citation: Diabetes Care. 2007 Aug;30(8):2001-2
references.pmid: 17473060
references.citation: Clin Ther. 2005 Sep;27(9):1432-43
references.pmid: 16291416
references.citation: Diabetes Care. 2007 May;30(5):1044-8
references.pmid: 17277042
references.citation: Clin Ther. 2007 Nov;29(11):2349-64
references.pmid: 18158076
references.citation: Clin Ther. 1999 Mar;21(3):523-34
references.pmid: 10321421
references.citation: Diabet Med. 2004 May;21(5):500-1
references.pmid: 15089801
references.citation: Eur J Intern Med. 2007 Jan;18(1):56-62
references.pmid: 17223044
references.citation: Diabetes Care. 2004 Dec;27(12):2806-12
references.pmid: 15562189
references.citation: J Diabetes Complications. 2006 May-Jun;20(3):145-52
references.pmid: 16632233
references.citation: Clin Ther. 2004 Jul;26(7):1179-81; discussion 1182-3
references.pmid: 15336483
references.citation: Curr Med Res Opin. 2007 Dec;23(12):3017-23
references.pmid: 17961295
references.citation: Curr Med Res Opin. 2002;18(4):188-93
references.pmid: 12201618
references.citation: J Assoc Physicians India. 2005 Sep;53:775-9
references.pmid: 16334621
references.citation: N Engl J Med. 2008 Jun 12;358(24):2545-59
references.pmid: 18539917
references.citation: JAMA. 2006 Apr 12;295(14):1688-97
references.pmid: 16609091
references.citation: Clin Ther. 2002 Apr;24(4):530-9
references.pmid: 12017398
references.citation: Lancet. 1998 Sep 12;352(9131):854-65
references.pmid: 9742977
references.citation: Diabetes Care. 2002 May;25(5):883-8
references.pmid: 11978685
references.citation: Diabetes Obes Metab. 2006 Jul;8(4):448-55
references.pmid: 16776752
references.citation: Diabetes Obes Metab. 2003 Sep;5(5):311-6
references.pmid: 12940868
references.citation: Rom J Intern Med. 2003;41(2):153-62
references.pmid: 15526500
references.citation: Clin Ther. 2003 Dec;25(12):3109-23
references.pmid: 14749149
references.citation: BMJ. 1997 Sep 13;315(7109):629-34
references.pmid: 9310563
references.citation: Diabet Med. 2005 Apr;22(4):374-81
references.pmid: 15787659
references.citation: Diabetes Metab. 2000 Dec;26(6):481-7
references.pmid: 11173719
references.citation: Diabetes Technol Ther. 2007 Jun;9(3):246-53
references.pmid: 17561795
references.citation: BMJ. 2004 Jun 19;328(7454):1490
references.pmid: 15205295
references.citation: S Afr Med J. 2003 Mar;93(3):219-23
references.pmid: 12768948
references.citation: Diabet Med. 2002 May;19(5):393-9
references.pmid: 12027927
references.citation: Diabetes Res Clin Pract. 2003 Feb;59(2):137-43
references.pmid: 12560163
references.citation: Horm Metab Res. 2005 Nov;37(11):684-9
references.pmid: 16308837
references.citation: Diabetes Care. 1997 Feb;20(2):163-9
references.pmid: 9118765
references.citation: Diabetes Obes Metab. 2003 Nov;5(6):446-54
references.pmid: 14617231
references.citation: Circulation. 1995 May 15;91(10):2591-5
references.pmid: 7743621
references.citation: Clin Ther. 2000 Feb;22(2):222-30
references.pmid: 10743981
references.citation: Diabetologia. 1999 Aug;42(8):926-31
references.pmid: 10491751
references.citation: Crit Care. 2008;12(1):R29
references.pmid: 18312617
references.citation: Diabetes Care. 1999 Aug;22(8):1258-61
references.pmid: 10480767
references.citation: Diabetes Obes Metab. 2006 Jan;8(1):39-48
references.pmid: 16367881
references.citation: Am J Epidemiol. 1986 Nov;124(5):719-23
references.pmid: 3766505
references.citation: Clin Ther. 2006 Oct;28(10):1649-57
references.pmid: 17157120
references.citation: Diabetes Res Clin Pract. 2003 Dec;62(3):187-95
references.pmid: 14625133
references.citation: Intern Med. 2007;46(18):1513-7
references.pmid: 17878636
references.citation: Exp Clin Endocrinol Diabetes. 2006 Oct;114(9):527-32
references.pmid: 17115351
references.citation: J Clin Epidemiol. 1997 Dec;50(12):1369-76
references.pmid: 9449940
references.citation: J Diabetes Complications. 2003 Nov-Dec;17(6):307-13
references.pmid: 14583174
references.citation: Eur J Intern Med. 2004 Dec;15(8):496-502
references.pmid: 15668084
references.citation: Health Qual Life Outcomes. 2007 Feb 07;5:8
references.pmid: 17286868
references.citation: Stat Med. 2007 Jan 15;26(1):53-77
references.pmid: 16596572
references.citation: N Engl J Med. 2007 Oct 25;357(17):1716-30
references.pmid: 17890232
references.citation: BMJ. 2003 Sep 6;327(7414):557-60
references.pmid: 12958120