Diabetes mellitus is an increasing health problem in the
world and our country. Medical nutrition, diet, exercise, patient education and medical treatment constitute major
solution methods for this problem. Insulin has a special
place among choices of medical treatment. In this article,
insulin analogues in treatment of diabetes mellitus were
reviewed. When glycemic control, hypoglycemia side effect and patient compliance to treatment are considered,
previous studies have shown that analogue insulins should
be preferred to human insulin. Insulin analogues have an
important role in medical treatment of diabetes mellitus.
1. United Kingdom Prospective Diabetes Study Group
Effect of intensive blood-glucose control with metformin
on complications in overweight patients with type 2
diabetes (UKPDS 34). Lancet,1998, 352:854–865
2. United Kingdom Prospective Diabetes Study Group
Intensive blood-glucose control with sulphonylureas or
insülin compared with conventional treatment and risk
of complications in patients with type 2 diabetes (UKPDS
33). Lancet,1998, 352:837–853
3. Ohkubo Y, Kishikawa H, Araki E et al. Intensive insülin
therapy prevents the progression of diabetic microvascular
complications in Japanese patients with non-insulindependent diabetes mellitus: a randomized prospective
6-year study. Diabetes Res Clin Pract, 1995, 28:103–117
4. Stratton IM, Adler AI, Neil HA et al. Association of
glycaemia with macrovascular and microvascular
complications of type 2 diabetes (UKPDS 35): prospective
observational study. BMJ,2000, 321:405–412
5. Gaede P, Vedel P, Larsen N et al. Multifactorial
intervention and cardiovascular disease in patients with
type 2 diabetes. N Engl J Med ,2003, 348:383–393
6. Genuth S, Eastman R, Kahn R et al. Implications of the
United kingdom prospective diabetes study. Diabetes
Care,2003, 26:S28–S32
7. Chiasson JL. Acarbose for the prevention of diabetes,
hypertension, and cardiovascular disease in subjects
with impaired glucose tolerance: the Study to Prevent
Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM)
Trial. Endocr Pract,2006, 12:25–30
8. Selvin E, Wattanakit K, Steffes MW, Coresh J, Sharrett
AR. HbA1c and peripheral arterial disease in diabetes:
the atherosclerosis risk in communities study. Diabetes
Care,2006, 29:877–882
9. Kirkman MS, McCarren M, Shah J, Duckworth W, Abraira
C. The association between metabolic control and
prevalent macrovascular disease in Type 2 diabetes:
the VA Cooperative Study in diabetes. J Diabetes
Complications,2006, 20:75–80
10. Martin S, Schneider B, Heinemann L et al. Selfmonitoring of blood glucose in type 2 diabetes and
long-term outcome: an epidemiological cohort study.
Diabetologia,2006, 49:271–278
11. American Diabetes Association. Standards of medical
care for patients with diabetes mellitus. Diabetes
Care,2003, 26:S33–S50
12. IDF Global Guideline for Type 2 Diabetes, 2011.
13. Satman İ et al. TURDEP II results. Turkish Endocrinology
and Metabolism Congress 2010
14. İlkova İ et al. IDMPS Turkey 3rd wave results – The profile
of Type 2 DM patients and the treatment methods.
National Diabetes Congress 2010
15. Barnett AH. A review of basal insulins. Diabet. Med,2003,
20, 873–885
16. Lepore M. et al. Pharmacokinetics and Pharmacodynamics
of Subcutaneous Injection of Long-Acting Human Insulin
Analog Glargine, NPH Insulin, and Ultralente Human
Insulin and Continuous Subcutaneous Infusion of Insulin
Lispro Diabetes,2000, 49:2142–2148
17. Ratner RE. et al. Less Hypoglycemia With Insulin Glargine
in Intensive Insulin Therapy for Type 1 Diabetes Diabetes
Care,2000, 23:639–643
18. Ashwell S.G. et al. Improved Glycaemic Control with Insulin
Glargine plus Insulin Lispro: A multicentre, Randomized,
Cross-over Trial in People with Type 1 Diabetes. Diabetic
Medicine,2006, 23, 285-292
19. Home P.D. et al. A randomized multicentre trial of insulin
glargine compared with NPH insulin in people with type 1
diabetes Diabetes Metab Res Rev 2005; 21: 545–553.
20. Raskin P. et al. A 16-Week Comparison of the Novel Insulin
Analog Insulin Glargine (HOE 901) and NPH Human
Insulin Used With Insulin Lispro in Patients With Type 1
Diabetes Diabetes Care,2000, 23:1666–1671
21. Benedetti M. et al. A One Year, Randomised, Multicentre
Trial Comparing Insulin Glargine with NPH Insulin in
Combination with Oral Agents in Patients with Type 2
Diabetes. Horm. Metab Res 2003;35: 189-196
22. Herwig J. et al. Glycaemic Control and Hypoglycaemia
in Children, Adolescents and Young Adults with Unstable
Type 1 Diabetes Mellitus Treated with Insulin Glargine
or Intermediate-acting Insulin Journal of Pediatrie
Endocrinology & Metabolisrn,2007, 20: 517-525
23. Mullins P. et al. Negative Binominal Meta-Regression
Analysis of Combned Glycosylated Hemoglobin and
Hypoglycaemia Outcomes Across Eleven Phase III and IV
Studies of Insulin Glargine Compared with NPH Insulin in
Type 1 and Type 2 DM. Clinical Therapeutics Volume 29,
Number 8, 2007; 1607-1619
24. White NH. et al. Comparison of Glycaemic Variability
Associated With Insulin Glargine and Intermediate-Acting
Insulin when used as the Basal Componennt of Multiple
Daily Injections for Adolescents With Type 1 Diabetes.
Diabetes Care,2009, 32:387-393
25. Fritsche A et al. Glimepiride Combined with Morning
Insulin Glargine, Bedtime Neutral Protamine Hagedorn
Insulin, or Bedtime Insulin Glargine in Patients with Type
2 Diabetes. Ann Intern Med. 2003;138:952-959.
26. Tsai ST et al. First Insulinization with Basal Insulin in
Patients with Type 2 Diabetes in a Real-world Setting in
Asia. Journal of Diabetes 3 ,2011, 208-216
27. Chase HP. et al. Insulin Glargine Versus IntermediateActing Insulin as the Basal Component of Multiple Daily
Injection Regimens for Adolescents with Type 1 Diabetes
Mellitus. 10.1016/j.jpeds.2008.04.063
28. Pan CY. et al. Insulin glargine versus NPH insulin therapy
in Asian Type 2 diabetes patients Diabetes Research and
Clinical Practice 76 ,2007, 111–118
29. Riddle MC. et al. The Treat-to-Target Trial Randomized
addition of glargine or human NPH insulin to oral
therapy of type 2 diabetic patients. Diabetes Care,2003,
26:3080–3086
30. Home P.D. et al. Meta-analysis of individual patient data
to assess the risk of hypoglycaemia in people with type 2
diabetes using NPH insulin or insulin glargine. Diabetes,
Obesity and Metabolism ,2010, 12:772-9.
31. Linn T. et al. Nocturnal Glucose Metabolism after Bedtime
Injection of Insulin Glargine or Neutral Protamine
Hagedorn Insulin in Patients with Type 2 Diabetes. J Clin
Endocrinol Metab,2008, 93: 3839–3846
32. Bolli G.B. et al. Lower fasting blood glucose, glucose
variability and nocturnal hypoglycaemia with glargine
vs NPH basal insulin in subjects with Type 1 diabetes.
Nutrition, Metabolism & Cardiovascular Diseases ,2009,
19: 571-579
33. Eliaschewitz F.G. et al. Therapy in Type 2 Diabetes:
Insulin Glargine vs. NPH Insulin Both in Combination
with Glimepiride. Archives of Medical Research,2006, 37:
495–501
34. Witthaus E. et al. Treatment satisfaction and psychological
well-being with insulin glargine compared with NPH in
patients with Type 1 diabetes. Diabetic Medicine,2001,
18: 619-625
35. Bradley C, Gilbride CJ. Improving treatment satisfaction
and other patient-reported outcomes in people with
type 2 diabetes: the role of once-daily insulin glargine.
Diabetes Obes Metab. 2008, Jul;10 Suppl 2:50-65
36. Schreiber S.A., Russmann A. Long-term efficacy of insülin
glargine therapy with an educational programme in type
1 diabetes patients in clinical practice. Current Medical
Research and Opinion, 2007, Vol. 23, No. 123131–3136
37. Gordon J et al. A comparison of intermediate and longacting insulins in people with type 2 diabetes starting
insulin: an observational database study. Int J Clin Pract,
2010, 64, 12, 1609–1618
38. Rhoads G. et al. Comparison of Incidence of Acute
Myocardial Infarction in Patients With Type 2 Diabetes
Mellitus Following Initiation of Neutral Protamine
Hagedorn Insulin Versus Insulin Glargine. Am J Cardiol,
2009;104:910 –916
39. Kurtzhals P. Engineering predictability and protraction
in a basal insulin analog: the pharmacology of insulin
detemir. Int J Obesity, 2004; 28 Suppl. 2: S23-8
41. Plank J, Bodenlenz M, Sinner F, et al. A double-blind,
randomized, dose-response study investigating the
pharmacodynamic and pharmacokinetic properties of the
long-acting insulin analog detemir. Diabetes Care ,2005;
28: 1107-12
42. Heise T, Nosek I, Rønn BB, et al. Lower within-subject
variability of insulin detemir in comparison to NPH insulin
and insulin glargine in people with type 1 diabetes.
diabetes. Diabetes ,2004; 53: 1614-20
43. Hermansen K. et al. Insulin analogues (insulin detemir
and insulin aspart) versus traditional human insulins
(NPH insulin and regular human insulin) in basal-bolus
therapy for patients with Type 1 diabetes. Diabetologia,
2004; 47:622–629
44. Dornhorst A, Lüddeke HJ, Sreenan S, et al. Safety and efficacy
of insulin detemir in clinical practice: 14-week follow-up data
from type 1 and type 2 diabetes patients in the PREDICTIVE
European cohort. Int J Clin Pract 2007; 61: 523 -8
45. Rašlová K, Bogoev M, Raz I, et al. Insulin detemir and
insulin aspart: a promising basal-bolus regimen for type 2
diabetes. Diabetes Res Clin Pract 2004 ; 66 (2): 193 -201.
Corrigendum: Diabetes Res Clin Pract 2006 ; 72 : 112
46. Haak T, Tiengo A, Draeger E, et al. Lower within-subject
variability of fasting blood glucose and reduced weight
gain with insulin detemir compared to NPH insulin in
patients with type 2 diabetes. Diabetes Obes Metab
2005 ; 7 : 56 -64
47. Fajardo Montañana C, Hernández Herrero C, Rivas
Fernández M. Less weight gain and hypoglycaemia with
once-daily insulin detemir than NPH insulin in intensifi
cation of insulin therapy in overweight type 2 diabetes
patients – the PREDICTIVE™ BMI clinical trial. Diabet
Med 2008
48. Hermansen K, Davies M, Derezinski T, et al. A 26-week,
randomized, parallel, treat-to-target trial comparing
insulin detemir with NPH insulin as add-on therapy to
oral glucose-lowering drugs in insulin-naive people with
type 2 diabetes. Diabetes Care 2006; 29 : 1269 -74
49. Philis-Tsimikas A, Charpentier G, Clauson P, et al.
Comparison of once-daily insulin detemir with NPH
insulin added to a regimen of oral antidiabetic drugs in
poorly controlled type 2 diabetes. Clin Ther 2006 ; 28 :
1569 -81
50. Holman RR, Thorne KI, Farmer AJ, et al. Addition of
biphasic, prandial, or basal insulin to oral therapy in type
2 diabetes. N Engl J Med 2007 ; 357 : 1716 -30
51. Rosenstock J, Davies M, Home P, et al. A randomised, 52-
week, treat-to-target trial comparing insulin detemir with
insulin glargine when added to glucose-lowering drugs in
insulin-naive people with type 2 diabetes. Diabetologia
2008;51: 408 -26
52. Meneghini L, Koenen C, Weng W, Selam J-L. The usage of a
simplifi ed self-titration dosing guideline (303 Algorithm)
for insulin detemir in patients with type 2 diabetes –
results of the randomized, controlled PREDICTIVE™ 303
study. Diabetes Obes Metab 2007 ; 9 : 902 -13
53. Athena Philis-Tsimikas. An update on the use of insulin
detemir, with a focus on type 2 diabetes (drug evaluation
update); Expert Opin. Pharmacother. 2008, 9(12):2181-2195
54. P. Valensi, E. Cosson, Is insulin detemir able to favor a
lower variability in the action of injected insulin in diabetic
subjects? Diabetes Metab. 2005 31: 4S34–4S39.
55. G.E. Peterson, Intermediate and long-acting insulins: a
review of NPH insulin, insulin glargine and insulin detemir,
Curr. Med. Res. Opin. 2006,22: 2613–2619.
56. K. Horvath, K. Jeitler, A. Berghold, S.H. Ebrahim, T.W.
Gratzer, J. Plank, et al. Long-acting insulin analogues
versus NPH insulin (human isophane insulin) for type 2
diabetes mellitus, Cochrane Database Syst. Rev.2007, 2
57. Heler S.et al Diversity in diabetes: the role of insulin
aspart Diabetes Metab Res Rev. 2012 Jan;28(1):50-61
58. Tamas G.Y et al. Glycaemic control in type 1 diabetic
patients using optimised insulin aspart or human insulin
in a randomised multinational study. Diabetes Research
and Clinical Practice 2001,54: 105–114.
59. NovoRapid Flexpen Kısa Ürün Bilgisi
60. Home PD, Lindholm A, Riis A; European Insulin Aspart
Study Group. Insulin aspart vs.human insulin in the
management of long-term blood glucose control in Type
1 diabetes mellitus: a randomized controlled trial. Diabet
Med 2000; 17: 762–770.
61. Raskin P, Guthrie RA, Leiter L, Riis A, Jovanovic L. Use
of insulin aspart, a fast-actinginsulin analog, as the
mealtime insulin in the management of patients with
type 1 diabetes. Diabetes Care 2000; 23: 583–588.
62. Bretzel RG, Arnolds S, Medding J, Linn T. A direct efficacy
and safety comparison of insulin aspart, human soluble
insulin, and human premix insulin (70/30) in patients with
type 2 diabetes. Diabetes Care 2004; 27: 1023–1027
63. Mathiesen ER, Kinsley B, Amiel SA, Heller S, McCance
D, Duran S, Bellaire S, Raben A. Maternal glycemic
control and hypoglycemia in type 1 diabetic pregnancy: a
randomized trial of insulin aspart versus human insulin in
322 pregnant women. Diabetes Care 2007;30(4):771-6
64. Heller SR, Colagiuri S, Vaaler S, et al. Hypoglycaemia
with insulin aspart: a doubleblind,randomised, crossover
trial in subjects with Type 1 diabetes. Diabet Med 2004;
21:769–775.
65. Wilde MI, McTavish D. Insulin lispro: a review of its
pharmacological properties and therapeutic use in the
management of diabetes mellitus. Drug 1997; 54:597-
614
66. Becker R. Frick AD, Burger F, Potgieter JH, Scholtz H.
Insulin glulisine, a new rapid-acting insulin analogue,
displays a rapid time-action profile in obese non-diabetic
subjects. Exp Clin Endocrinol Diabetes 2005; 113:435-
443
67. Becker R. Insulin glulisine complementing basal insulins:
a review of structure and activity. Diabetes Technology
Ther 2007;9: 109-121
68. Becker R. Frick AD, Nosek L, Heinemann L, Rave K. Doseresponse relationship of insulin glulisine in subjects with
type 1 diabetes. Diabetes Care 2007;30:2506-2507
69. Garg SK, Rosenstock J, Ways K. Optimized Basal-bolus
insulin regimens in type 1 diabetes: insulin glulisine
versus regular human insulin in combination with Basal
insulin glargine. Endocr Pract 2005;11: 11-17
70. Dailey G, Rosenstock J, Moses RG, Ways K. Insulin glulisine
provides improved glycemic control in patients with type
2 diabetes. Diabetes Care 2004; 27 : 2363-2368
71. Danne T. Becker RH, Heise T, Bittner C, Frick AD, Rave K.
Pharmacokinetics, prandial glucose control, and safety of
insulin glulisine in children and adolescents with type 1
diabetes.Diabetes Care 2005; 28: 2100-2105
72. Raymen G, Profozic V, Middle M. Insulin glulisine imparts
effective glycaemic control in patients with Type 2
diabetes. Diabetes Res Clin Pract. 2007 ; 76:304-312.
73. Overmann H, Heinemann L. Injection-meal interval:
recommendations of diabetologists and how patients
handle it. Diab Res Clin Pract 1999;43:137
74. Raskin P et al. Initiation of insulin therapy in patients
with type 2 diabetes failing oral therapy. Diab Care 2005;
28:2811
75. Weyer C, Heise T, Heinemann L. Insulin aspart in a 30/70
premixed formulation. Pharmacodynamic properties of
a rapid-acting insulin analog in stable mixture. Diabetes
Care ,1997, Vol.20, No.10 , 1612-1614
76. Jacobsen L.V,Sogaard B., Riis A. Pharmacokinetics
and pharmacodynamics of a premixed formulation of
soluble and protamine-retarded insulin aspart. Eur J Clin
Pharmacol 2000, 56;399-403
77. Home P.D, Barriconal L,Lindholm A. Comparative
pharmacokinetics and pharmacodynamics of the novel
rapid-acting insulin analogue, insulin aspart, in healthy
volunteers. Eur J Clin Pharmacol 1999, 55:199-203
78. Heise T, Heinemann L, Hövelmann U, Brauns B, Nosek
L, Haahr HL, Olsen KJ Biphasic insulin aspart 30/70:
pharmacokinetics and pharmacodynamics compared
with once-daily biphasic human insulin and Basal-bolus
therapy.Diabetes Care 2009 32:1431-1443
79. McNally P G, Dean J D, Morris A.D, Wilkinson P D,Compion
G, Heller S R. Using continuous glucose monitoring to
measure the frequency of low glucose values when using
biphasic insulin aspart 30 compared with biphasic human
insulin 30: a double-blind crossover study in individuals
with type 2 diabetes Diabetes Care 2007, Vol 30, No 5,
1044-1048
80. Boehm B O, Home P.D., Behrendt C.,Kampt N.M., Lindholmt A.
Premixed insulin aspart 30 vs. premixed human insulin 30/70
twice daily: a randomized trial in Type 1 and Type 2 diabetic
patients. 2002, Diabetes UK, Diabetes Medicine;19,393-399
81. Boehm B. O, Vaz J.A,Brondsted L, Home P.D, Long-term
efficacy and safety of biphasic insulin aspart in patients
with type 2 diabetes. European Journal of Internal
Medicine ,2004,15: 496-502
82. Shestakova M, Sharma S.K, Almustafa M, Min K.W,
Ayad N, Azar S.T, Danciulescu R. et al. Transferring type
2 diabetes patients with uncontrolled glycaemia from
biphasic human insulin to biphasic insulin aspart 30:
experiences from the PRESENT study. Current Medical
Research and Opinion 2007, Vol 23, No.12, 3209-3214
83. McSorley P T,Bell P M, Jacobsen L V, Kristiensen A,
Lindholm A Clinical Therapeutics. Twice-daily biphasic
insulin aspart 30 versus biphasic human insulin 30:
a double-blind crossover study in adults with type 2
diabetes mellitus. 2002 Vol 24,No.4, 530-539
84. Kapitza C,Rave K, Ostrowski K et al Reduced postprandial
glycaemic excursion with biphasic insulin Aspart 30
injected immediately before a meal. Diabet Med
2004;21:500-501
85. Garber A, Wahlen J, Wahl T, Bressler P, Braceras R, Allen E,
Jain R. Attainment of glycaemic goals in type 2 diabetes
with once-, twice-, or thrice-daily dosing with biphasic
insulin aspart 70/30 (The 1-2-3 study). Diabetes, Obesity
and Metabolism 2006;8(1):58-66
86. Ligthelm R J.Primary Care Diabetes. Self-titration of
biphasic insulin aspart 30/70 improves glycaemic control
and allows easy intensification in a Dutch clinical practice
2009 3,97-102
87. Unnikrishnan A.G, Tibaldi J, Hadley- Brown M, Krentz A.J,
Ligthelm R J, Damcı T. Practical guidance on intensification
of insulin therapy with BIAsp 30: a consensus statement
Int J Clin Pract. 2009 Nov;63(11):1571-7
88. Wilde MI, McTavish D. Insulin lispro: a review of its
pharmacological properties and therapeutic use in the
management of diabetes mellitus. Drug 1997; 54:597-
614
89. Koivisto VA, Tuominen JA, Ebeling P. Lispro Mix25 Insulin
As Premeal Therapy in Type 2 Diabetic Patients Diabetes
Care 1999;22:459–462)
İnsülin Analoglarının Diyabetes Mellitus Tedavisindeki Rolü ve Faydaları
Diyabetes Mellitus (DM) ülkemizde ve dünyada giderek artan bir sağlık problemidir. Tıbbi beslenme, diyet, egzersiz, hasta eğitimi ve medikal tedavi bu problemin çözüm yöntemleridir. Medikal tedavi seçenekleri içinde insülin tedavisi özel bir yer tutmaktadır. Bu yazıda diyabetes mellitus tedavisinde insülin analogları ele alınmıştır. Glisemik kontrol, hipoglisemi yan etkisi, tedavi uyumu kriter olarak alınırsa, İnsan insülini ile insülin analogları karşılaştırıldığında analog insülinlerin tercih edilmesi gerektiği yapılan çalışmalardan anlaşılmaktadır. İnsülin analogları diyabetes mellitusun medikal tedavisinde önemli bir yere sahiptir.
1. United Kingdom Prospective Diabetes Study Group
Effect of intensive blood-glucose control with metformin
on complications in overweight patients with type 2
diabetes (UKPDS 34). Lancet,1998, 352:854–865
2. United Kingdom Prospective Diabetes Study Group
Intensive blood-glucose control with sulphonylureas or
insülin compared with conventional treatment and risk
of complications in patients with type 2 diabetes (UKPDS
33). Lancet,1998, 352:837–853
3. Ohkubo Y, Kishikawa H, Araki E et al. Intensive insülin
therapy prevents the progression of diabetic microvascular
complications in Japanese patients with non-insulindependent diabetes mellitus: a randomized prospective
6-year study. Diabetes Res Clin Pract, 1995, 28:103–117
4. Stratton IM, Adler AI, Neil HA et al. Association of
glycaemia with macrovascular and microvascular
complications of type 2 diabetes (UKPDS 35): prospective
observational study. BMJ,2000, 321:405–412
5. Gaede P, Vedel P, Larsen N et al. Multifactorial
intervention and cardiovascular disease in patients with
type 2 diabetes. N Engl J Med ,2003, 348:383–393
6. Genuth S, Eastman R, Kahn R et al. Implications of the
United kingdom prospective diabetes study. Diabetes
Care,2003, 26:S28–S32
7. Chiasson JL. Acarbose for the prevention of diabetes,
hypertension, and cardiovascular disease in subjects
with impaired glucose tolerance: the Study to Prevent
Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM)
Trial. Endocr Pract,2006, 12:25–30
8. Selvin E, Wattanakit K, Steffes MW, Coresh J, Sharrett
AR. HbA1c and peripheral arterial disease in diabetes:
the atherosclerosis risk in communities study. Diabetes
Care,2006, 29:877–882
9. Kirkman MS, McCarren M, Shah J, Duckworth W, Abraira
C. The association between metabolic control and
prevalent macrovascular disease in Type 2 diabetes:
the VA Cooperative Study in diabetes. J Diabetes
Complications,2006, 20:75–80
10. Martin S, Schneider B, Heinemann L et al. Selfmonitoring of blood glucose in type 2 diabetes and
long-term outcome: an epidemiological cohort study.
Diabetologia,2006, 49:271–278
11. American Diabetes Association. Standards of medical
care for patients with diabetes mellitus. Diabetes
Care,2003, 26:S33–S50
12. IDF Global Guideline for Type 2 Diabetes, 2011.
13. Satman İ et al. TURDEP II results. Turkish Endocrinology
and Metabolism Congress 2010
14. İlkova İ et al. IDMPS Turkey 3rd wave results – The profile
of Type 2 DM patients and the treatment methods.
National Diabetes Congress 2010
15. Barnett AH. A review of basal insulins. Diabet. Med,2003,
20, 873–885
16. Lepore M. et al. Pharmacokinetics and Pharmacodynamics
of Subcutaneous Injection of Long-Acting Human Insulin
Analog Glargine, NPH Insulin, and Ultralente Human
Insulin and Continuous Subcutaneous Infusion of Insulin
Lispro Diabetes,2000, 49:2142–2148
17. Ratner RE. et al. Less Hypoglycemia With Insulin Glargine
in Intensive Insulin Therapy for Type 1 Diabetes Diabetes
Care,2000, 23:639–643
18. Ashwell S.G. et al. Improved Glycaemic Control with Insulin
Glargine plus Insulin Lispro: A multicentre, Randomized,
Cross-over Trial in People with Type 1 Diabetes. Diabetic
Medicine,2006, 23, 285-292
19. Home P.D. et al. A randomized multicentre trial of insulin
glargine compared with NPH insulin in people with type 1
diabetes Diabetes Metab Res Rev 2005; 21: 545–553.
20. Raskin P. et al. A 16-Week Comparison of the Novel Insulin
Analog Insulin Glargine (HOE 901) and NPH Human
Insulin Used With Insulin Lispro in Patients With Type 1
Diabetes Diabetes Care,2000, 23:1666–1671
21. Benedetti M. et al. A One Year, Randomised, Multicentre
Trial Comparing Insulin Glargine with NPH Insulin in
Combination with Oral Agents in Patients with Type 2
Diabetes. Horm. Metab Res 2003;35: 189-196
22. Herwig J. et al. Glycaemic Control and Hypoglycaemia
in Children, Adolescents and Young Adults with Unstable
Type 1 Diabetes Mellitus Treated with Insulin Glargine
or Intermediate-acting Insulin Journal of Pediatrie
Endocrinology & Metabolisrn,2007, 20: 517-525
23. Mullins P. et al. Negative Binominal Meta-Regression
Analysis of Combned Glycosylated Hemoglobin and
Hypoglycaemia Outcomes Across Eleven Phase III and IV
Studies of Insulin Glargine Compared with NPH Insulin in
Type 1 and Type 2 DM. Clinical Therapeutics Volume 29,
Number 8, 2007; 1607-1619
24. White NH. et al. Comparison of Glycaemic Variability
Associated With Insulin Glargine and Intermediate-Acting
Insulin when used as the Basal Componennt of Multiple
Daily Injections for Adolescents With Type 1 Diabetes.
Diabetes Care,2009, 32:387-393
25. Fritsche A et al. Glimepiride Combined with Morning
Insulin Glargine, Bedtime Neutral Protamine Hagedorn
Insulin, or Bedtime Insulin Glargine in Patients with Type
2 Diabetes. Ann Intern Med. 2003;138:952-959.
26. Tsai ST et al. First Insulinization with Basal Insulin in
Patients with Type 2 Diabetes in a Real-world Setting in
Asia. Journal of Diabetes 3 ,2011, 208-216
27. Chase HP. et al. Insulin Glargine Versus IntermediateActing Insulin as the Basal Component of Multiple Daily
Injection Regimens for Adolescents with Type 1 Diabetes
Mellitus. 10.1016/j.jpeds.2008.04.063
28. Pan CY. et al. Insulin glargine versus NPH insulin therapy
in Asian Type 2 diabetes patients Diabetes Research and
Clinical Practice 76 ,2007, 111–118
29. Riddle MC. et al. The Treat-to-Target Trial Randomized
addition of glargine or human NPH insulin to oral
therapy of type 2 diabetic patients. Diabetes Care,2003,
26:3080–3086
30. Home P.D. et al. Meta-analysis of individual patient data
to assess the risk of hypoglycaemia in people with type 2
diabetes using NPH insulin or insulin glargine. Diabetes,
Obesity and Metabolism ,2010, 12:772-9.
31. Linn T. et al. Nocturnal Glucose Metabolism after Bedtime
Injection of Insulin Glargine or Neutral Protamine
Hagedorn Insulin in Patients with Type 2 Diabetes. J Clin
Endocrinol Metab,2008, 93: 3839–3846
32. Bolli G.B. et al. Lower fasting blood glucose, glucose
variability and nocturnal hypoglycaemia with glargine
vs NPH basal insulin in subjects with Type 1 diabetes.
Nutrition, Metabolism & Cardiovascular Diseases ,2009,
19: 571-579
33. Eliaschewitz F.G. et al. Therapy in Type 2 Diabetes:
Insulin Glargine vs. NPH Insulin Both in Combination
with Glimepiride. Archives of Medical Research,2006, 37:
495–501
34. Witthaus E. et al. Treatment satisfaction and psychological
well-being with insulin glargine compared with NPH in
patients with Type 1 diabetes. Diabetic Medicine,2001,
18: 619-625
35. Bradley C, Gilbride CJ. Improving treatment satisfaction
and other patient-reported outcomes in people with
type 2 diabetes: the role of once-daily insulin glargine.
Diabetes Obes Metab. 2008, Jul;10 Suppl 2:50-65
36. Schreiber S.A., Russmann A. Long-term efficacy of insülin
glargine therapy with an educational programme in type
1 diabetes patients in clinical practice. Current Medical
Research and Opinion, 2007, Vol. 23, No. 123131–3136
37. Gordon J et al. A comparison of intermediate and longacting insulins in people with type 2 diabetes starting
insulin: an observational database study. Int J Clin Pract,
2010, 64, 12, 1609–1618
38. Rhoads G. et al. Comparison of Incidence of Acute
Myocardial Infarction in Patients With Type 2 Diabetes
Mellitus Following Initiation of Neutral Protamine
Hagedorn Insulin Versus Insulin Glargine. Am J Cardiol,
2009;104:910 –916
39. Kurtzhals P. Engineering predictability and protraction
in a basal insulin analog: the pharmacology of insulin
detemir. Int J Obesity, 2004; 28 Suppl. 2: S23-8
41. Plank J, Bodenlenz M, Sinner F, et al. A double-blind,
randomized, dose-response study investigating the
pharmacodynamic and pharmacokinetic properties of the
long-acting insulin analog detemir. Diabetes Care ,2005;
28: 1107-12
42. Heise T, Nosek I, Rønn BB, et al. Lower within-subject
variability of insulin detemir in comparison to NPH insulin
and insulin glargine in people with type 1 diabetes.
diabetes. Diabetes ,2004; 53: 1614-20
43. Hermansen K. et al. Insulin analogues (insulin detemir
and insulin aspart) versus traditional human insulins
(NPH insulin and regular human insulin) in basal-bolus
therapy for patients with Type 1 diabetes. Diabetologia,
2004; 47:622–629
44. Dornhorst A, Lüddeke HJ, Sreenan S, et al. Safety and efficacy
of insulin detemir in clinical practice: 14-week follow-up data
from type 1 and type 2 diabetes patients in the PREDICTIVE
European cohort. Int J Clin Pract 2007; 61: 523 -8
45. Rašlová K, Bogoev M, Raz I, et al. Insulin detemir and
insulin aspart: a promising basal-bolus regimen for type 2
diabetes. Diabetes Res Clin Pract 2004 ; 66 (2): 193 -201.
Corrigendum: Diabetes Res Clin Pract 2006 ; 72 : 112
46. Haak T, Tiengo A, Draeger E, et al. Lower within-subject
variability of fasting blood glucose and reduced weight
gain with insulin detemir compared to NPH insulin in
patients with type 2 diabetes. Diabetes Obes Metab
2005 ; 7 : 56 -64
47. Fajardo Montañana C, Hernández Herrero C, Rivas
Fernández M. Less weight gain and hypoglycaemia with
once-daily insulin detemir than NPH insulin in intensifi
cation of insulin therapy in overweight type 2 diabetes
patients – the PREDICTIVE™ BMI clinical trial. Diabet
Med 2008
48. Hermansen K, Davies M, Derezinski T, et al. A 26-week,
randomized, parallel, treat-to-target trial comparing
insulin detemir with NPH insulin as add-on therapy to
oral glucose-lowering drugs in insulin-naive people with
type 2 diabetes. Diabetes Care 2006; 29 : 1269 -74
49. Philis-Tsimikas A, Charpentier G, Clauson P, et al.
Comparison of once-daily insulin detemir with NPH
insulin added to a regimen of oral antidiabetic drugs in
poorly controlled type 2 diabetes. Clin Ther 2006 ; 28 :
1569 -81
50. Holman RR, Thorne KI, Farmer AJ, et al. Addition of
biphasic, prandial, or basal insulin to oral therapy in type
2 diabetes. N Engl J Med 2007 ; 357 : 1716 -30
51. Rosenstock J, Davies M, Home P, et al. A randomised, 52-
week, treat-to-target trial comparing insulin detemir with
insulin glargine when added to glucose-lowering drugs in
insulin-naive people with type 2 diabetes. Diabetologia
2008;51: 408 -26
52. Meneghini L, Koenen C, Weng W, Selam J-L. The usage of a
simplifi ed self-titration dosing guideline (303 Algorithm)
for insulin detemir in patients with type 2 diabetes –
results of the randomized, controlled PREDICTIVE™ 303
study. Diabetes Obes Metab 2007 ; 9 : 902 -13
53. Athena Philis-Tsimikas. An update on the use of insulin
detemir, with a focus on type 2 diabetes (drug evaluation
update); Expert Opin. Pharmacother. 2008, 9(12):2181-2195
54. P. Valensi, E. Cosson, Is insulin detemir able to favor a
lower variability in the action of injected insulin in diabetic
subjects? Diabetes Metab. 2005 31: 4S34–4S39.
55. G.E. Peterson, Intermediate and long-acting insulins: a
review of NPH insulin, insulin glargine and insulin detemir,
Curr. Med. Res. Opin. 2006,22: 2613–2619.
56. K. Horvath, K. Jeitler, A. Berghold, S.H. Ebrahim, T.W.
Gratzer, J. Plank, et al. Long-acting insulin analogues
versus NPH insulin (human isophane insulin) for type 2
diabetes mellitus, Cochrane Database Syst. Rev.2007, 2
57. Heler S.et al Diversity in diabetes: the role of insulin
aspart Diabetes Metab Res Rev. 2012 Jan;28(1):50-61
58. Tamas G.Y et al. Glycaemic control in type 1 diabetic
patients using optimised insulin aspart or human insulin
in a randomised multinational study. Diabetes Research
and Clinical Practice 2001,54: 105–114.
59. NovoRapid Flexpen Kısa Ürün Bilgisi
60. Home PD, Lindholm A, Riis A; European Insulin Aspart
Study Group. Insulin aspart vs.human insulin in the
management of long-term blood glucose control in Type
1 diabetes mellitus: a randomized controlled trial. Diabet
Med 2000; 17: 762–770.
61. Raskin P, Guthrie RA, Leiter L, Riis A, Jovanovic L. Use
of insulin aspart, a fast-actinginsulin analog, as the
mealtime insulin in the management of patients with
type 1 diabetes. Diabetes Care 2000; 23: 583–588.
62. Bretzel RG, Arnolds S, Medding J, Linn T. A direct efficacy
and safety comparison of insulin aspart, human soluble
insulin, and human premix insulin (70/30) in patients with
type 2 diabetes. Diabetes Care 2004; 27: 1023–1027
63. Mathiesen ER, Kinsley B, Amiel SA, Heller S, McCance
D, Duran S, Bellaire S, Raben A. Maternal glycemic
control and hypoglycemia in type 1 diabetic pregnancy: a
randomized trial of insulin aspart versus human insulin in
322 pregnant women. Diabetes Care 2007;30(4):771-6
64. Heller SR, Colagiuri S, Vaaler S, et al. Hypoglycaemia
with insulin aspart: a doubleblind,randomised, crossover
trial in subjects with Type 1 diabetes. Diabet Med 2004;
21:769–775.
65. Wilde MI, McTavish D. Insulin lispro: a review of its
pharmacological properties and therapeutic use in the
management of diabetes mellitus. Drug 1997; 54:597-
614
66. Becker R. Frick AD, Burger F, Potgieter JH, Scholtz H.
Insulin glulisine, a new rapid-acting insulin analogue,
displays a rapid time-action profile in obese non-diabetic
subjects. Exp Clin Endocrinol Diabetes 2005; 113:435-
443
67. Becker R. Insulin glulisine complementing basal insulins:
a review of structure and activity. Diabetes Technology
Ther 2007;9: 109-121
68. Becker R. Frick AD, Nosek L, Heinemann L, Rave K. Doseresponse relationship of insulin glulisine in subjects with
type 1 diabetes. Diabetes Care 2007;30:2506-2507
69. Garg SK, Rosenstock J, Ways K. Optimized Basal-bolus
insulin regimens in type 1 diabetes: insulin glulisine
versus regular human insulin in combination with Basal
insulin glargine. Endocr Pract 2005;11: 11-17
70. Dailey G, Rosenstock J, Moses RG, Ways K. Insulin glulisine
provides improved glycemic control in patients with type
2 diabetes. Diabetes Care 2004; 27 : 2363-2368
71. Danne T. Becker RH, Heise T, Bittner C, Frick AD, Rave K.
Pharmacokinetics, prandial glucose control, and safety of
insulin glulisine in children and adolescents with type 1
diabetes.Diabetes Care 2005; 28: 2100-2105
72. Raymen G, Profozic V, Middle M. Insulin glulisine imparts
effective glycaemic control in patients with Type 2
diabetes. Diabetes Res Clin Pract. 2007 ; 76:304-312.
73. Overmann H, Heinemann L. Injection-meal interval:
recommendations of diabetologists and how patients
handle it. Diab Res Clin Pract 1999;43:137
74. Raskin P et al. Initiation of insulin therapy in patients
with type 2 diabetes failing oral therapy. Diab Care 2005;
28:2811
75. Weyer C, Heise T, Heinemann L. Insulin aspart in a 30/70
premixed formulation. Pharmacodynamic properties of
a rapid-acting insulin analog in stable mixture. Diabetes
Care ,1997, Vol.20, No.10 , 1612-1614
76. Jacobsen L.V,Sogaard B., Riis A. Pharmacokinetics
and pharmacodynamics of a premixed formulation of
soluble and protamine-retarded insulin aspart. Eur J Clin
Pharmacol 2000, 56;399-403
77. Home P.D, Barriconal L,Lindholm A. Comparative
pharmacokinetics and pharmacodynamics of the novel
rapid-acting insulin analogue, insulin aspart, in healthy
volunteers. Eur J Clin Pharmacol 1999, 55:199-203
78. Heise T, Heinemann L, Hövelmann U, Brauns B, Nosek
L, Haahr HL, Olsen KJ Biphasic insulin aspart 30/70:
pharmacokinetics and pharmacodynamics compared
with once-daily biphasic human insulin and Basal-bolus
therapy.Diabetes Care 2009 32:1431-1443
79. McNally P G, Dean J D, Morris A.D, Wilkinson P D,Compion
G, Heller S R. Using continuous glucose monitoring to
measure the frequency of low glucose values when using
biphasic insulin aspart 30 compared with biphasic human
insulin 30: a double-blind crossover study in individuals
with type 2 diabetes Diabetes Care 2007, Vol 30, No 5,
1044-1048
80. Boehm B O, Home P.D., Behrendt C.,Kampt N.M., Lindholmt A.
Premixed insulin aspart 30 vs. premixed human insulin 30/70
twice daily: a randomized trial in Type 1 and Type 2 diabetic
patients. 2002, Diabetes UK, Diabetes Medicine;19,393-399
81. Boehm B. O, Vaz J.A,Brondsted L, Home P.D, Long-term
efficacy and safety of biphasic insulin aspart in patients
with type 2 diabetes. European Journal of Internal
Medicine ,2004,15: 496-502
82. Shestakova M, Sharma S.K, Almustafa M, Min K.W,
Ayad N, Azar S.T, Danciulescu R. et al. Transferring type
2 diabetes patients with uncontrolled glycaemia from
biphasic human insulin to biphasic insulin aspart 30:
experiences from the PRESENT study. Current Medical
Research and Opinion 2007, Vol 23, No.12, 3209-3214
83. McSorley P T,Bell P M, Jacobsen L V, Kristiensen A,
Lindholm A Clinical Therapeutics. Twice-daily biphasic
insulin aspart 30 versus biphasic human insulin 30:
a double-blind crossover study in adults with type 2
diabetes mellitus. 2002 Vol 24,No.4, 530-539
84. Kapitza C,Rave K, Ostrowski K et al Reduced postprandial
glycaemic excursion with biphasic insulin Aspart 30
injected immediately before a meal. Diabet Med
2004;21:500-501
85. Garber A, Wahlen J, Wahl T, Bressler P, Braceras R, Allen E,
Jain R. Attainment of glycaemic goals in type 2 diabetes
with once-, twice-, or thrice-daily dosing with biphasic
insulin aspart 70/30 (The 1-2-3 study). Diabetes, Obesity
and Metabolism 2006;8(1):58-66
86. Ligthelm R J.Primary Care Diabetes. Self-titration of
biphasic insulin aspart 30/70 improves glycaemic control
and allows easy intensification in a Dutch clinical practice
2009 3,97-102
87. Unnikrishnan A.G, Tibaldi J, Hadley- Brown M, Krentz A.J,
Ligthelm R J, Damcı T. Practical guidance on intensification
of insulin therapy with BIAsp 30: a consensus statement
Int J Clin Pract. 2009 Nov;63(11):1571-7
88. Wilde MI, McTavish D. Insulin lispro: a review of its
pharmacological properties and therapeutic use in the
management of diabetes mellitus. Drug 1997; 54:597-
614
89. Koivisto VA, Tuominen JA, Ebeling P. Lispro Mix25 Insulin
As Premeal Therapy in Type 2 Diabetic Patients Diabetes
Care 1999;22:459–462)