Review Article
Why and How to Use Insulin Therapy Earlier in the Management of Type 2 Diabetes
Abstract
Most patients with type 2 diabetes are inadequately controlled on their current therapy. Suboptimal glycemic control can have devastating consequences, such as retinopathy, nephropathy, neuropathy, and cardiovascular disease that may ultimately lead to mortality. Most patients eventually need insulin therapy, and initiating insulin earlier in the course of type 2 diabetes may lead to optimal glycemic control and prevent or delay diabetes-related complications. Although insulin therapy is the most effective method of managing hyperglycemia, it is often delayed owing to concerns about the complexity and inconvenience of treatment regimens; fear of injections, hypoglycemia or weight gain; and the time required to learn how to effectively manage insulin therapy. The development of insulin analogs, biphasic insulin analogs, and more convenient insulin delivery systems may make insulin therapy more manageable and help more patients achieve their treatment goals.
Key Points
* Current approaches to managing type 2 diabetes that delay the use of insulin often fail to provide effective glycemic control.
* Initiating insulin earlier in the course of treatment may improve glycemic control, which may prevent or delay the development of diabetes-related complications.
* The greater safety and convenience of insulin analogs compared to regular human insulin therapies may help reduce resistance to initiating insulin among patients and practitioners and facilitate the earlier use of insulin therapy.
This content is limited to qualifying members.
Existing members, please login first
If you have an existing account please login now to access this article or view purchase options.
Purchase only this article ($25)
Create a free account, then purchase this article to download or access it online for 24 hours.
Purchase an SMJ online subscription ($75)
Create a free account, then purchase a subscription to get complete access to all articles for a full year.
Purchase a membership plan (fees vary)
Premium members can access all articles plus recieve many more benefits. View all membership plans and benefit packages.
References
1. Koro CE, Bowlin SJ, Bourgeois N, et al. Glycemic control from 1988 to 2000 among US adults diagnosed with type 2 diabetes: a preliminary report. Diabetes Care 2004;27:17–20.
2. United Kingdom Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin 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 insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent 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. Nathan DM. Clinical practice: initial management of glycemia in type 2 diabetes mellitus. N Engl J Med 2002;347:1342–1349.
6. Riddle M. Introduction. Am J Med 2000;108(suppl 6A):1.
7. Brown JB, Nichols GA, Perry A. The burden of treatment failure in type 2 diabetes. Diabetes Care 2004;27:1535–1540.
8. Eldor R, Stern E, Milicevic Z, et al. Early use of insulin in type 2 diabetes. Diabetes Res Clin Pract 2005;68(suppl 1):S30–S35.
9. Marre M. Before oral agents fail: the case for starting insulin early. Int J Obes Relat Metab Disord 2002;26(Suppl 3):S25–S30.
10. Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977–986.
11. Writing Team for the Diabetes Control Trial. Effect of intensive therapy on the microvascular complications of type 1 diabetes mellitus. JAMA 2002;287:2563–2569.
12. Nathan DM, Cleary PA, Backlund JY, et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005;353:2643–2653.
13. DECODE Study Group: European Diabetes Epidemiology Group. Is the current definition for diabetes relevant to mortality risk from all causes and cardiovascular and noncardiovascular diseases? Diabetes Care 2003;26:688–696.
14. Hanefeld M, Fischer S, Julius U, et al. Risk factors for myocardial infarction and death in newly detected NIDDM: the diabetes intervention study, 11-year follow-up. Diabetologia 1996;39:1577–1583.
15. Nathan DM, Lachin J, Cleary P, et al. Intensive diabetes therapy and carotid intima-media thickness in type 1 diabetes mellitus. N Engl J Med 2003;348:2294–2303.
16. Selvin E, Coresh J, Golden SH, et al. Glycemic control and coronary heart disease risk in persons with and without diabetes: the atherosclerosis risk in communities study. Arch Intern Med 2005;165:1910–1916.
17. Hughes TA, Clements RS, Fairclough PK, et al. Effect of insulin therapy on lipoproteins in non-insulin dependent diabetes mellitus (NIDDM). Atherosclerosis 1987;67:105–114.
18. Meneghini LF, Schwartz S, Soltes RE, et al. Improved glycemic control with insulin glargine (GLAR) vs pioglitazone (PIO) as add-on therapy in patients with type 2 diabetes (T2D) uncontrolled on sulfoylurea (SU) or metformin (MET) monotherapy (abstract 10-LB). Diabetes 2005;54 (Suppl 1).
19. Rask-Madsen C, Ihlemann N, Krarup T, et al. Insulin therapy improves insulin-stimulated endothelial function in patients with type 2 diabetes and ischemic heart disease. Diabetes 2001;50:2611–2618.
20. Chaudhuri A, Kanjwal Y, Mohanty P, et al. Insulin-induced vasodilatation of internal carotid artery. Metabolism 1999;48:1470–1473.
21. Dandona P, Aljada A, Mohanty P. The anti-inflammatory and potential anti-atherogenic effect of insulin: a new paradigm. Diabetologia 2002;45:924–930.
22. Melidonis A, Stefanidis A, Tournis S, et al. The role of strict metabolic control by insulin infusion on fibrinolytic profile during an acute coronary event in diabetic patients. Clin Cardiol 2000;23:160–164.
23. Jonassen AK, Sack MN, Mjos OD, et al. Myocardial protection by insulin at reperfusion requires early administration and is mediated via Akt and p70s6 kinase cell-survival signaling. Circ Res 2001;89:1191–1198.
24. Dailey G. New strategies for basal insulin treatment in type 2 diabetes mellitus. Clin Ther 2004;26:889–901.
25. Garvey WT, Olefsky JM, Griffin J, et al. The effect of insulin treatment on insulin secretion and insulin action in type II diabetes mellitus. Diabetes 1985;34:222–234.
26. Robertson RP, Olson LK, Zhang HJ. Differentiating glucose toxicity from glucose desensitization: a new message from the insulin gene. Diabetes 1994;43:1085–1089.
27. Robertson RP, Harmon J, Tran PO, et al. Glucose toxicity in beta-cells: type 2 diabetes, good radicals gone bad, and the glutathione connection. Diabetes 2003;52:581–587.
28. Glaser B, Leibovich G, Nesher R, et al. Improved beta-cell function after intensive insulin treatment in severe non-insulin-dependent diabetes. Acta Endocrinol (Copenh) 1988;118:365–373.
29. Andrews WJ, Vasquez B, Nagulesparan M, et al. Insulin therapy in obese, non-insulin-dependent diabetes induces improvements in insulin action and secretion that are maintained for two weeks after insulin withdrawal. Diabetes 1984;33:634–642.
30. Ilkova H, Glaser B, Tunckale A, et al. Induction of long-term glycemic control in newly diagnosed type 2 diabetic patients by transient intensive insulin treatment. Diabetes Care 1997;20:1353–1356.
31. Ryan EA, Imes S, Wallace C. Short-term intensive insulin therapy in newly diagnosed type 2 diabetes. Diabetes Care 2004;27:1028–1032.
32. Rolla A. The pathophysiological basis for intensive insulin replacement. Int J Obes Relat Metab Disord. 2004;28 (Suppl 2):S3–S7.
33. Alvarsson M, Sundkvist G, Lager I, et al. Beneficial effects of insulin versus sulphonylurea on insulin secretion and metabolic control in recently diagnosed type 2 diabetic patients. Diabetes Care 2003;26:2231–2237.
34. Hirsch IB, Brownlee M. Should minimal blood glucose variability become the gold standard of glycemic control? J Diabetes Complications 2005;19:178–181.
35. Monnier L, Lapinski H, Colette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA(1c). Diabetes Care 2003;26:881–885.
36. Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes 2005;54:1615–1625.
37. Wild SH, Smith FB, Lee AJ, et al. Criteria for previously undiagnosed diabetes and risk of mortality: 15-year follow-up of the Edinburgh Artery Study cohort. Diabet Med 2005;22:490–496.
38. de Vegt F, Dekker JM, Ruhe HG, et al. Hyperglycaemia is associated with all-cause and cardiovascular mortality in the Hoorn population: the Hoorn study. Diabetologia 1999;42:926–931.
39. Menzin J, Langley-Hawthorne C, Friedman M, et al. Potential short-term economic benefits of improved glycemic control: a managed care perspective. Diabetes Care 2001;24:51–55.
40. Gilmer TP, O’Connor PJ, Manning WG, et al. The cost to health plans of poor glycemic control. Diabetes Care 1997;20:1847–1853.
41. Pibernik-Okanovic M, Szabo S, Metelko Z. Quality of life following a change in therapy for diabetes mellitus. Pharmacoeconomics 1998;14:201–207.
42. Oglesby AK, Secnik K, Barron J, et al. The association between diabetes related medical costs and glycemic control: a retrospective analysis. Cost Eff Resour Alloc 2006;4:1.
43. Schwartz S, Sievers R, Strange P, et al. Insulin 70/30 mix plus metformin versus triple oral therapy in the treatment of type 2 diabetes after failure of two oral drugs: efficacy, safety, and cost analysis. Diabetes Care 2003;26:2238–2243.
44. DeWitt DE, Hirsch IB. Outpatient insulin therapy in type 1 and type 2 diabetes mellitus: scientific review. JAMA 2003;289:2254–2264.
45. Chow CC, Tsang LW, Sorensen JP, et al. Comparison of insulin with or without continuation of oral hypoglycemic agents in the treatment of secondary failure in NIDDM patients. Diabetes Care1995;18:307–314.
46. Taylor R, Foster B, Kyne-Grzebalski D, et al. Insulin regimens for the non-insulin dependent: impact on diurnal metabolic state and quality of life. Diabet Med 1994;11:551–557.
47. Taylor R, Davies R, Fox C, et al. Appropriate insulin regimes for type 2 diabetes: a multicenter randomized crossover study. Diabetes Care 2000;23:1612–1618.
48. Palumbo PJ. The case for insulin treatment early in type 2 diabetes. Cleve Clin J Med 2004;71:385–394.
49. Tanenberg RJ. Transitioning pharmacologic therapy from oral agents to insulin for type 2 diabetes.Curr Med Res Opin 2004;20:541–553.
50. Birkeland KI, Hanssen KF, Urdal P, et al. A long-term, randomized, comparative study of insulin versus sulfonylurea therapy in type 2 diabetes. J Intern Med 1994;236:305–313.
51. Davis T, Edelman SV. Insulin therapy in type 2 diabetes. Med Clin North Am 2004;88:865–895.
52. Wright A, Burden AC, Paisey RB, et al. Sulfonylurea inadequacy: efficacy of addition of insulin over 6 years in patients with type 2 diabetes in the UK Prospective Diabetes Study (UKPDS 57). Diabetes Care 2002;25:330–336.
53. Johnson JL, Wolf SL, Kabadi UM. Efficacy of insulin and sulfonylurea combination therapy in type II diabetes: a meta-analysis of the randomized placebo-controlled trials. Arch Intern Med 1996;156:259–264.
54. King SA. On managing pain in older persons. J Am Geriatr Soc 1999;47:119–123.
55. Pyorala M, Miettinen H, Laakso M, et al. Hyperinsulinemia predicts coronary heart disease risk in healthy middle-aged men: the 22-year follow-up results of the Helsinki Policemen Study. Circulation 1998;98:398–404.
56. Abraira C, Colwell J, Nuttall F, et al. Cardiovascular events and correlates in the veterans affairs diabetes feasibility trial. Veterans Affairs Cooperative Study on Glycemic Control and Complications in Type II Diabetes. Arch Intern Med 1997;157:181–188.
57. Malmberg K. Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. BMJ 1997;314:1512–1515.
58. Malmberg K, Ryden L, Wedel H, et al. Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity. Eur Heart J 2005;26:650–661.
59. Moss SE, Klein R, Klein BE, et al. The association of glycemia and cause-specific mortality in a diabetic population. Arch Intern Med 1994;154:2473–2479.
60. Hellman R, Regan J, Rosen H. Effect of intensive treatment of diabetes of the risk of death or renal failure in NIDDM and IDDM. Diabetes Care 1997;20:258–264.
61. Shah BR, Hux JE, Laupacis A, et al. Clinical inertia in response to inadequate glycemic control: do specialists differ from primary care physicians? Diabetes Care 2005;28:600–606.
62. Peyrot M, Rubin RR, Lauritzen T, et al. Resistance to insulin therapy among patients and providers: results of the cross-national Diabetes Attitudes, Wishes, and Needs (DAWN) study. Diabetes Care 2005;28:2673–2679.
63. Mollema ED, Snoek FJ, Ader HJ, et al. Insulin-treated diabetes patients with fear of self-injecting or fear of self-testing: psychological comorbidity and general well-being. J Psychosom Res 2001;51:665–672.
64. Rolla AR, Rakel RE. Practical approaches to insulin therapy for type 2 diabetes mellitus with premixed insulin analogues. Clin Ther 2005;27:1113–1125.
65. Bohannon NJ, Ohannesian JP, Burdan AL, et al. Patient and physician satisfaction with the Humulin/Humalog Pen, a new 3.0-mL prefilled pen device for insulin delivery. Clin Ther 2000;22:1049–1067.
66. Korytkowski M, Bell D, Jacobsen C, et al. A multicenter, randomized, open-label, comparative, two-period crossover trial of preference, efficacy, and safety profiles of a prefilled, disposable pen and conventional vial/syringe for insulin injection in patients with type 1 or 2 diabetes mellitus. Clin Ther 2003;25:2836–2848.
67. Summers KH, Szeinbach SL, Lenox SM. Preference for insulin delivery systems among current insulin users and nonusers. Clin Ther 2004;26:1498–1505.
68. Brunton SA, White JR Jr, Renda SM. The role of basal insulin in type 2 diabetes management. J Fam Pract 2005;Oct(Suppl) S1–S8.
69. Bastyr EJ III, Stuart CA, Brodows RG, et al. Therapy focused on lowering postprandial glucose, not fasting glucose, may be superior for lowering HbA1c. Diabetes Care 2000;23:1236–1241.
70. American Diabetes Association. Standards of medical care in diabetes-2006. Diabetes Care 2006; 29(Suppl 1):S4–S42.
71. International Diabetes Federation. Global Guideline for Type 2 Diabetes. Brussels, 2005. Available at: http://www.idf.org/home/index.cfm?note=1457. Accessed January 2, 2007.
72. American Association of Clinical Endocrinologists. The American Association of Clinical Endocrinologists medical guidelines for the management of diabetes mellitus: the AACE system of intensive diabetes self-management: 2002 update. Endocr Pract 2002;8(Suppl 1):40–82.
73. Yki-Jarvinen H, Dressler A, Ziemen M. Less nocturnal hypoglycemia and better post-dinner glucose control with bedtime insulin glargine compared with bedtime NPH insulin during insulin combination therapy in type 2 diabetes. Diabetes Care 2000;23:1130–1136.
74. De Leeuw I, Vague P, Selam J-L, et al. Insulin detemir used in basal-bolus therapy in people with type 1 diabetes is associated with a lower risk of nocturnal hypoglycaemia and less weight gain over 12 months in comparison to NPH insulin. Diabetes Obes Metab 2005;7:73–82.
75. Heise T, Nosek L, Ronn 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 2004;53:1614–1620.
76. Riddle MC, Rosenstock J, Gerich J. 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.
77. Rosenstock J, Schwartz SL, Clark CM Jr, et al. Basal insulin therapy in type 2 diabetes: 28-week comparison of insulin glargine (HOE 901) and NPH insulin. Diabetes Care 2001;24:631–636.
78. Home P, Bartley P, Russell-Jones D, et al. Insulin detemir offers improved glycemic control compared with NPH insulin in people with type 1 diabetes: a randomized clinical trial. Diabetes Care 2004;27:1081–1087.
79. 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.
80. Russell-Jones D, Simpson R, Hylleberg B, et al. Effects of QD insulin detemir or neutral protamine Hagedorn on blood glucose control in patients with type I diabetes mellitus using a basal-bolus regimen.Clin Ther 2004;26:724–736.
81. Pieber TR, Draeger E, Kristensen A, et al. Comparison of three multiple injection regimens for type 1 diabetes: morning plus dinner or bedtime administration of insulin detemir vs. morning plus bedtime NPH insulin. Diabet Med 2005;22:850–857.
82. Raslova K, Bogoev M, Raz I, et al. Insulin detemir and insulin aspart: a promising basal-bolus regimen for type 2 diabetes. [Correction appears in Raslova K, Diabetes Res Clin Pract. 2006;72:112]. Diabetes Res Clin Pract 2004;66:193–201.
83. Hermansen K, Fontaine P, Kukolja KK, 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.
84. Hermansen K, Derezinski T, Kim H, et al. Treatment with insulin detemir in combination with oral agents is associated with less risk of hypoglycaemia and less weight gain than NPH insulin at comparable levels of glycaemic improvement in people with type 2 diabetes (abstract). Diabetologia2004;47(Suppl 1):A273–A274.
85. Pfutzner A, Kustner E, Forst T, et al. Intensive insulin therapy with insulin lispro in patients with type 1 diabetes reduces the frequency of hypoglycemic episodes. Exp Clin Endocrinol Diabetes 1996;104: 25–30.
86. Brange J, Volund A. Insulin analogs with improved pharmacokinetic profiles. Adv Drug Deliv Rev 1999;35:307–335.
87. Vazquez-Carrera M, Silvestre JS. Insulin analogues in the management of diabetes. Methods Find Exp Clin Pharmacol 2004;26:445–461.
88. Hirsch IB. Intensifying insulin therapy in patients with type 2 diabetes mellitus. Am J Med 2005;118(suppl 5A):21S–26S.
89. Lindholm A, McEwen J, Riis AP. Improved postprandial glycemic control with insulin aspart: a randomized double-blind cross-over trial in type 1 diabetes. Diabetes Care 1999;22:801–805.
90. Danne T, Aman J, Schober E, et al. A comparison of postprandial and preprandial administration of insulin aspart in children and adolescents with type 1 diabetes. Diabetes Care 2003;26:2359–2364.
91. Jovanovic L, Giammattei J, Acquistapace M, et al. Efficacy comparison between preprandial and postprandial insulin aspart administration with dose adjustment for unpredictable meal size. Clin Ther 2004;26:1492–1497.
92. Warren ML, Conway MJ, Klaff LJ, et al. Postprandial versus preprandial dosing of biphasic insulin aspart in elderly type 2 diabetes patients. Diabetes Res Clin Pract 2004;66:23–29.
93. Schernthaner G, Wein W, Sandholzer K, et al. Postprandial insulin lispro: a new therapeutic option for type 1 diabetic patients. Diabetes Care 1998;21:570–573.
94. Roach P, Trautmann M, Arora V, et al. Improved postprandial blood glucose control and reduced nocturnal hypoglycemia during treatment with two novel insulin-protamine formulations, insulin lispro Mix25. Clin Ther 1999;21:523–534.
95. Boehm BO, Home PD, Behrend C, et al. Premixed insulin aspart 30 vs premixed human insulin 30/70 twice daily: a randomized trial in Type 1 and Type 2 diabetic patients. Diabet Med 2002;19:393–399.
96. Boehm BO, Vaz JA, Brondsted L, et al. Long-term efficacy and safety of biphasic insulin aspart in patients with type 2 diabetes. Eur J Intern Med 2004;15:496–502.
97. Weissberg-Benchell J, Antisdel-Lomaglio J, Seshadri R. Insulin pump therapy: a meta-analysis. Diabetes Care 2003;26:1079–1087.
98. Pickup J, Keen H. Continuous subcutaneous insulin infusion at 25 years: evidence base for the expanding use of insulin pump therapy in type 1 diabetes. Diabetes Care 2002;25:593–598.
99. Pickup J, Mattock M, Kerry S. Glycaemic control with continuous subcutaneous insulin infusion compared with intensive insulin injections in patients with type 1 diabetes: meta-analysis of randomised controlled trials. BMJ 2002;324:705.
100. Graff MR, Rubin RR, Walker EA. How diabetes specialists treat their own diabetes: findings from a study of the AADE and ADA membership. Diabetes Educ 2000;46:460–467.
101. Meece J. Dispelling myths and removing barriers about insulin in type 2 diabetes. Diabetes Educ 2006;32:9S–18S.
102. Makimattila S, Nikkila K, Yki-Jarvinen H. Causes of weight gain during insulin therapy with and without metformin in patients with Type II diabetes mellitus. Diabetologia 1999;42:406–412.
103. Davies M, Storms F, Shutler S, et al. Improvement of glycemic control in subjects with poorly controlled type 2 diabetes: comparison of two treatment algorithms using insulin glargine. Diabetes Care 2005;28:1282–1288.
104. Kamal AD, Dixon AN, Bain SC. Safety and side effects of the insulin analogues. Expert Opin Drug Safety 2006;5:131–143.
105. 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;28:1107–1112.
106. Eli Lilly and Company. Humalog Mix 75/25 (75% insulin lispro protamine suspension and 25% insulin lispro injection [rDNA origin]) [prescribing information]. Indianapolis, Eli Lilly and Company. 2005.
107. Novo Nordisk. Levemir (insulin detemir [rDNA origin] injection) [product information]. Princeton, Novo Nordisk A/S. June 16, 2005.
108. Novo Nordisk: NovoLog Mix 70/30 (70% insulin aspart protamine suspension and 30% insulin aspart injection [rDNA origin]) [product information]. Princeton, Novo Nordisk Inc, 2005.
109. LaSalle JR. New insulin analogs: insulin detemir and insulin glulisine. Pract Diabetol 2006;25:34–44.
110. Daugherty KK. Review of insulin therapy. J Pharm Practice 2004;17:10–19.
111. Kilo C, Mezitis N, Jain R, et al. Starting patients with type 2 diabetes on insulin therapy using once-daily injections of biphasic insulin aspart 70/30, biphasic human insulin 70/30, or NPH insulin in combination with metformin. J Diabetes Complications 2003;17:307–313.
112. Garber AJ, Wahlen J, Wahl T, et al. 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 Obes Metab2006;8:58–66.
