Glycemic variability: Too often overlooked in type 2 diabetes?

,

Applied Evidence

Glycemic variability: Too often overlooked in type 2 diabetes?

J Fam Pract. 2010 August;59(8):E1-E8

PDF Download

References

1. Koro CE, Bowlin SJ, Bourgeois N, et al. Glycemic control from 1988 to 2000 among U.S. adults diagnosed with type 2 diabetes: a preliminary report. Diabetes Care. 2004;27:17-20.

2. Kadowaki S, Okamura T, Hozawa A, et al. Relationship of elevated casual blood glucose level with coronary heart disease, cardiovascular disease and all-cause mortality in a representative sample of the Japanese population. NIPPON DATA80. Diabetologia. 2008;51:575-582.

3. Wändell PE, Theobald H. The association between low fasting glucose value and mortality. Curr Diabetes Rev. 2007;3:274-279.

4. Wei M, Gibbons LW, Mitchell TL, et al. Low fasting plasma glucose level as a predictor of cardiovascular disease and all-cause mortality. Circulation. 2000;101:2047-2052.

5. Hirsch IB, Brownlee M. Should minimal blood glucose variability become the gold standard of glycemic control? J Diabetes Complications. 2005;19:178-181.

6. Temelkova-Kurktschiev TS, Koehler C, Henkel E, et al. Postchallenge plasma glucose and glycemic spikes are more strongly associated with atherosclerosis than fasting glucose or HbA1c level. Diabetes Care. 2000;23:1830-1834.

7. Bonora E, Muggeo M. Postprandial blood glucose as a risk factor for cardiovascular disease in Type II diabetes: the epidemiological evidence. Diabetologia. 2001;44:2107-2114.

8. Chiasson JL, Josse RG, Gomis R, et al. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial. JAMA. 2003;290:486-494.

9. Meigs JB, Nathan DM, D’Agostino RB, Sr, et al. Fasting and postchallenge glycemia and cardiovascular disease risk: the Framingham Offspring Study. Diabetes Care. 2002;25:1845-1850.

10. Balkau B, Shipley M, Jarrett RJ, et al. High blood glucose concentration is a risk factor for mortality in middle-aged nondiabetic men. 20-year follow-up in the Whitehall Study, the Paris Prospective Study, and the Helsinki Policemen Study. Diabetes Care. 1998;21:360-367.

11. 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.

12. Donahue RP, Abbott RD, Reed DM, et al. Postchallenge glucose concentration and coronary heart disease in men of Japanese ancestry. Honolulu Heart Program. Diabetes. 1987;36:689-692.

13. Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria. The DECODE study group. European Diabetes Epidemiology Group. Diabetes Epidemiology: Collaborative analysis Of Diagnostic criteria in Europe. Lancet. 1999;354:617-621.

14. Balkau B, Hu G, Qiao Q, et al. Prediction of the risk of cardiovascular mortality using a score that includes glucose as a risk factor. The DECODE Study. Diabetologia. 2004;47:2118-2128.

15. 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.

16. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993;329:977-986.

17. 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.

18. The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545-2559.

19. The ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560-2572.

20. Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360:129-139.

21. Miller ME, Bonds DE, Gerstein HC, et al. The effects of baseline characteristics, glycaemia treatment approach, and glycated haemoglobin concentration on the risk of severe hypoglycaemia: post hoc epidemiological analysis of the ACCORD study. BMJ. 2010;340:b5444.-

22. Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577-1589.

23. Turnbull FM, Abraira C, Anderson RJ, et al. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia. 2009;11:2288-2298.

24. 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.

25. Standards of medical care in diabetes—2010 Diabetes Care. 2010;33(suppl 1):S11-S61.

26. Barnett AH. Treating to goal: challenges of current management. Eur J Endocrinol. 2004;151(suppl 2):T3-T7.

27. Brown JB, Nichols GA, Perry A. The burden of treatment failure in type 2 diabetes. Diabetes Care. 2004;27:1535-1540.

28. Nathan DM. Clinical practice. Initial management of glycemia in type 2 diabetes mellitus. N Engl J Med. 2002;347:1342-1349.

29. Nathan DM, Buse JB, Davidson MB, et al. American Diabetes Association; European Association for the Study of Diabetes. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care. 2009;32:193-203.

30. Chaudhuri A, Janicke D, Wilson MF, et al. Anti-inflammatory and profibrinolytic effect of insulin in acute ST-segment-elevation myocardial infarction. Circulation. 2004;109:849-854.

31. 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.

32. Chaudhuri A, Kanjwal Y, Mohanty P, et al. Insulin-induced vasodilatation of internal carotid artery. Metabolism. 1999;48:1470-1473.

33. 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.

34. 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.

35. Rolla A. The pathophysiological basis for intensive insulin replacement. Int J Obes Relat Metab Disord. 2004;28(suppl 2):S3-S7.

36. 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.

37. 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.

38. 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.

39. Ryan EA, Imes S, Wallace C. Short-term intensive insulin therapy in newly diagnosed type 2 diabetes. Diabetes Care. 2004;27:1028-1032.

40. Heise T, Heinemann L. Rapid and long-acting analogues as an approach to improve insulin therapy: an evidence-based medicine assessment. Curr Pharm Des. 2001;7:1303-1325.

41. Brems DN, Alter LA, Beckage MJ, et al. Altering the association properties of insulin by amino acid replacement. Protein Eng. 1992;5:527-533.

42. Garber AJ. Pharmacologic modifications of hormones to improve their therapeutic potential for diabetes management. Diabetes Obes Metab. 2005;7:666-674.

43. Hansen BF, Danielsen GM, Drejer K, et al. Sustained signalling from the insulin receptor after stimulation with insulin analogues exhibiting increased mitogenic potency. Biochem J. 1996;315(pt 1):271-279.

44. Slieker LJ, Brooke GS, DiMarchi RD, et al. Modifications in the B10 and B26-30 regions of the B chain of human insulin alter affinity for the human IGF-I receptor more than for the insulin receptor. Diabetologia. 1997;40(suppl 2):S54-S61.

45. Dimitriadis GD, Gerich JE. Importance of timing of preprandial subcutaneous insulin administration in the management of diabetes mellitus. Diabetes Care. 1983;6:374-377.

46. Roy B, Chou MC, Field JB. Time-action characteristics of regular and NPH insulin in insulin-treated diabetics. J Clin Endocrinol Metab. 1980;50:475-479.

47. Binder C, Lauritzen T, Faber O, et al. Insulin pharmacokinetics. Diabetes Care. 1984;7:188-199.

48. Kang S, Creagh FM, Peters JR, et al. Comparison of subcutaneous soluble human insulin and insulin analogues (AspB9, GluB27; AspB10; AspB28) on meal-related plasma glucose excursions in type 1 diabetic subjects. Diabetes Care. 1991;14:571-577.

49. Becker RH, Frick AD, Burger F, et al. A comparison of the steady-state pharmacokinetics and pharmacodynamics of a novel rapid-acting insulin analog, insulin glulisine, and regular human insulin in healthy volunteers using the euglycemic clamp technique. Exp Clin Endocrinol Diabetes. 2005;113:292-297.

50. Hirsch IB. Insulin analogues. N Engl J Med. 2005;352:174-183.

51. 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.

52. Brunelle BL, Llewelyn J, Anderson JH, Jr, et al. Meta-analysis of the effect of insulin lispro on severe hypoglycemia in patients with type 1 diabetes. Diabetes Care. 1998;21:1726-1731.

53. Home PD, Lindholm A, Hylleberg B, et al. Improved glycemic control with insulin aspart: a multicenter randomized double-blind crossover trial in type 1 diabetic patients. UK Insulin Aspart Study Group. Diabetes Care. 1998;21:1904-1909.

54. Heise T, Pieber TR. Towards peakless, reproducible and long-acting insulins. An assessment of the basal analogues based on isoglycaemic clamp studies. Diabetes Obes Metab. 2007;5:648-659.

55. Bolli GB, Di Marchi RD, Park GD, et al. Insulin analogues and their potential in the management of diabetes mellitus. Diabetologia. 1999;42:1151-1167.

56. Klein O, Lynge J, Endahl L, et al. Albumin-bound basal insulin analogues (insulin detemir and NN344): comparable time-action profiles but less variability than insulin glargine in type 2 diabetes. Diabetes Obes Metab. 2007;9:290-299.

57. 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.

58. 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. HOE 901/3002 Study Group. Diabetes Care. 2000;23:1130-1136.

59. 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.

60. 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;29:1269-1274.

61. 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;28:1569-1581.

62. 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.

63. Lepore M, Pampanelli S, Fanelli C, 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.

64. 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.

65. Ginsberg HN. Insulin resistance and cardiovascular disease. J Clin Invest. 2000;106:453-458.

66. Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes. 2005;54:1615-1625.

67. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001;414:813-820.

68. Ceriello A. Coagulation activation in diabetes mellitus: the role of hyperglycaemia and therapeutic prospects. Diabetologia. 1993;36:1119-1125.

69. Quagliaro L, Piconi L, Assaloni R, et al. Intermittent high glucose enhances apoptosis related to oxidative stress in human umbilical vein endothelial cells: the role of protein kinase C and NAD(P)H-oxidase activation. Diabetes. 2003;52:2795-2804.

70. Jones SC, Saunders HJ, Qi W, et al. Intermittent high glucose enhances cell growth and collagen synthesis in cultured human tubulointerstitial cells. Diabetologia. 1999;42:1113-1119.

71. Risso A, Mercuri F, Quagliaro L, et al. Intermittent high glucose enhances apoptosis in human umbilical vein endothelial cells in culture. Am J Physiol Endocrinol Metab. 2001;281:E924-E930.

72. Monnier L, Mas E, Ginet C, et al. Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes. JAMA. 2006;295:1681-1687.

Long-acting agents
Basal, or long-acting, insulins are important for maintaining normoglycemia over 24 hours. Neutral protamine Hagedorn (NPH) insulin reaches its peak effect 4 to 10 hours after injection, and its total effect lasts only 12 to 18 hours. NPH is therefore often dosed twice daily. Absorption of NPH can vary significantly, causing day-to-day blood glucose fluctuations.^46,47 Therefore, this agent’s activity does not closely resemble normal physiologic basal insulin secretion.

FAST TRACK

Long-acting insulin analogs stay active up to 24 hours without pronounced peaks, permitting once-daily dosing in many patients.

The newer long-acting insulin analogs—insulin detemir and insulin glargine—were designed to more closely replicate normal physiologic basal insulin secretion. Insulin glargine was first to reach the market, in 2001. It contains glycine instead of asparagine in the alpha-chain and 2 arginine residues at the C-terminus, and the addition of zinc enhances the aggregation and slow release at a neutral pH. Insulin glargine precipitates in the subcutaneous tissue, which slows its absorption and results in a relatively flat insulin plasma profile and extended action.^54,55 Insulin detemir is a combination of the original insulin molecule and a saturated fatty acid (myristic acid). Insulin detemir is designed to bind albumin (98% albumin-bound in circulation) through this fatty acid chain in the plasma after injection, resulting in an extended plasma profile.^54,56 Insulin glargine and NPH form crystalline depots, but detemir is soluble and the subcutaneous depot remains in a liquid state; this may account for differences in absorption variability.⁵⁶

FAST TRACK

In head-to-head comparisons, insulin detemir has demonstrated less within-subject variability of blood glucose levels than insulin glargine.

Advantages of the long-acting insulin analogs. Compared with conventional basal insulin such as NPH, the analogs have a prolonged duration of action (up to 24 hours) without pronounced peaks, permitting once-daily dosing in many patients (TABLE 2 and FIGURE 2).^46,47,50,55 The pharmacodynamic and pharmacokinetic properties of the long- acting agents make them less likely than NPH to cause nocturnal and overall hypoglycemia, a benefit that has been observed in several clinical trials.^57-61

Comparative clinical trials evaluating glycemic variability. Both of the long-acting analogs have shown lower within-subject variability in blood and plasma glucose measurements when compared with NPH.^62-64 In head-to-head comparisons of the analogs in glucose clamp studies, insulin detemir has demonstrated less within-subject variability of blood glucose levels than insulin glargine, in patients with T1DM or T2DM.^56,64 In clinical practice, different patients may have better results with one of these basal insulins as opposed to the other, and treatment choices will need to be tailored to the individual patient.

TABLE 2
Pharmacokinetic properties giving insulin analogs an advantage over regular insulin^46-50

Insulin preparation	Onset of action	Peak action	Duration of action
Short-acting
Regular	30-60 minutes	2-3 hours	8-10 hours
Lispro	5-15 minutes	30-90 minutes	4-6 hours
Aspart	5-15 minutes	30-90 minutes	4-6 hours
Glulisine	20 minutes	90 minutes	5.3 hours
Long-acting
NPH	2-4 hours	4-10 hours	12-18 hours
Glargine	2-4 hours	Relatively flat	Up to 24 hours
Detemir	1-2 hours	Relatively flat	Up to 24 hours
NPH, neutral protamine Hagedorn.

FIGURE 2
Pharmacokinetic profiles of human insulin and insulin analogs

Adapted from: Burton S. J Fam Pract. 2006;55(12 suppl):S10-S17.

CORRESPONDENCE Eric L. Johnson, MD, University of North Dakota School of Medicine and Health Sciences, Department of Family & Community Medicine, 501 North Columbia Road, Grand Forks, ND 58202-9037; ejohnson@medicine.nodak.edu