Glycemic Variability and the Role It Should Play in Diabetes Management and Blood Glucose Monitoring

Glycemic Variability and the Role It Should Play in Diabetes Management and Blood Glucose Monitoring

Bode Bruce W
US Endocrinology - Volume 4 - Issue II
Published: April 2009
download article

| More
dots

Diabetes is estimated to affect 23.6 million people in the US.1 It is characterized by hyperglycemia, which is partly responsible for the development of diabetic complications such as nephropathy, retinopathy, heart disease, and stroke.1–3 Glucose levels are generally stable in healthy people; however, they are quite variable in patients with diabetes. This glycemic variability in patients with diabetes involves interprandial hypoglycemia and periods of post-prandial and acute hyperglycemia.2,4 Factors influencing glycemic variability include deficiency of endogenous insulin and amylin secretion,5,6 lack of appropriate suppression of glucagon upon eating, poor compliance with diet and exercise therapy,7 and inappropriate use of exogenous insulin and other hypoglycemic agents.8,9

Glycemic variability is typically measured by self-monitoring of blood glucose (SMBG),10–16 although continuous glucose monitoring (CGM) systems are now a US Food and Drug Administration (FDA)-approved alternative.17 SMBG is a well-established blood glucose monitoring system10–16 and can be performed in the clinic or at home.18,19 It involves intermittent fingerstick measurements to obtain immediate blood glucose values throughout the day.18,19 Diabetes management software can analyze these data and subsequently calculate the standard deviation (SD) of blood glucose values (the square root of the variance).20 SD is a measure of glycemic variability, where high SD may indicate several problems, including insulin deficiency or excess, poor matching of calories with insulin, late administration of mealtime insulin (or missing injections completely), erratic snacking, the need for insulin pump therapy, etc.4 SMBG also allows identification of abnormal glucose values, such as hypo- (nadir) and hyperglycemic (peak) periods.16,17 Thus, the use of SMBG along with this software would allow patients to modify their treatment regimen and obtain better glycemic control.17,21 The ideal target SD is: SD x 3 < mean glucose; however, this target is hard to achieve in type 1 diabetes.4 A simple target to strive for is: SD x 2 < mean glucose.4 On the other hand, the relatively new CGM devices involve continuous glucose monitoring of interstitial fluid,17 which can be used to calculate the mean amplitude of glucose excursion (MAGE), representing intraday glycemic variability,17 and mean of the daily differences, representing interday variability.22 CGM use in type 1 diabetes is becoming more common; however, very little data on its use in type 2 diabetes have been published.

Diabetes management has evolved from the days of bovine and porcine insulin, with the introduction of rapid- and long-acting analogs of human insulin that provide a better simulation of endogenous insulin levels for diabetic patients using insulin. Patients with type 2 diabetes are now served by an increasing variety of oral antidiabetic agents, with many of the newer agents having the advantage of being glucose-dependent in their mechanism of action, thus reducing the risk for hypoglycemia and, thereby, glycemic variability. Hyperglycemia is established as a risk factor for diabetesrelated complications,11 and the comprehensive Diabetes Complications and Control Trial (DCCT)11,20 and United Kingdom Prospective Diabetes Study (UKPDS)23 have established the long-term benefits of intensive glycemic control for reducing the risk for microvascular complications. Since glycated hemoglobin (HbA1c) is a marker of glycemia,24–26 the American Diabetes Association’s (ADA’s) current recommended treatment target is to achieve a HbA1c level <7%,27 with the goal of achieving near-normoglycemia without hypoglycemia.28 There is mounting evidence that glycemic variability is linked to long-term diabetic complications,4 which would appear to necessitate a review of current diabetes management regimens. This article examines the latest evidence and also discusses the role of glycemic variability in diabetes management and blood glucose monitoring.

12345next ›last »
References:
  1. National Diabetes Fact Sheet, 2007, Available at: www.cdc.gov/diabetes/pubs/pdf/ndfs_2007.pdf (accessed December 2008).
  2. Monnier L, Colette C, Glycemic variability: should we and can we prevent it?, Diabetes Care, 2008;31(Suppl. 2):S150–54.
  3. American Diabetes Association, Standards of medical care in diabetes, Diabetes Care, 2004;27:S15–35.
  4. Hirsch IB, Glycemic Variability: It’s Not Just About A1C Anymore!, Diabetes Technol Ther, 2005;7(5):780–83.
  5. Reynolds C, Molnar GD, Horwitz DL, et al., Abnormalities of endogenous glucagon and insulin in unstable diabetes, Diabetes, 1977;26:36–45.
  6. The Diabetes Control and Complications Trial Research Group, Effect of intensive therapy on residual beta-cell function in patients with type 1 diabetes in the diabetes control and complications trial, A randomized, controlled trial, Ann Intern Med, 1998;28:517–23.
  7. Tattersall R, Gregory R, Selby C, et al., Course of brittle diabetes: 12 year follow up, BMJ, 1991;302:1240–43.
  8. Schade DS, Drumm DA, Duckworth WC, The etiology of incapacitating, brittle diabetes, Diabetes Care, 1985;8:12–20.
  9. Morris AD, Boyle DI, McMahon AD, et al., Adherence to insulin treatment, glycaemic control, and ketoacidosis in insulindependent diabetes mellitus. The DARTS/MEMO Collaboration. Diabetes Audit and Research in Tayside Scotland, Medicines Monitoring Unit, Lancet, 1997;350:1505–10.
  10. Bode BW, Gross TM, Thornton KR, et al., Continuous glucose monitoring used to adjust diabetes therapy improves glycosylated hemoglobin: a pilot study, Diabetes Res Clin Pract, 1999;46(3):183–90.
  11. DCCT, 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(14):977–86.
  12. Welschen LM, Bloemendal E, Nijpels G, et al., Self-monitoring of blood glucose in patients with type 2 diabetes who are not using insulin, Cochrane Database Syst Rev, 2005;(2):CD005060.
  13. Nathan DM, McKitrick C, Larkin M, et al., Glycemic control in diabetes mellitus: have changes in therapy made a difference?, Am J Med, 1996;100(2):157–63.
  14. Karter AJ, Ackerson LM, Darbinian JA, et al., Self-monitoring of blood glucose levels and glycemic control: the Northern California Kaiser Permanente Diabetes registry, Am J Med, 2001;111(1):1–9.
  15. ADA, Test of glycemia in diabetes, Diabetes Care, 1998;21: S69–71.
  16. Graham R, Self-Monitoring of Blood Glucose (SMBG): Considerations for Intensive Diabetes Management, Pharmaceutical and Therapeutics (Supplement), 2005; 30(12).
  17. Girardin CM, Huot C, Gonthier M, et al., Continuous glucose monitoring: A review of biochemical perspectives and clinical use in type 1 diabetes, Clin Biochem, 2008;11 [Epub ahead of print].
  18. Hirsch IB, Bode BW, Childs BP, et al., Self-Monitoring of Blood Glucose (SMBG) in insulin- and non-insulin-using adults with diabetes: Consensus recommendations for improving SMBG accuracy, utilization, and research, Diabetes Technol Ther, 2008;10(6):419–39.
  19. Christopher D, Saudek; Rachel L, et al., Assessing Glycemia in Diabetes Using Self-monitoring Blood Glucose and Hemoglobin A1c, JAMA, 2006;295(14):1688–97.
  20. Hirsch IB, Brownlee M, Should minimal blood glucose variability become the gold standard of glycemic control?, J Diabetes Complications, 2005;19(3):178–81.
  21. Karter AJ, Parker MM, Moffet HH, et al., Longitudinal study of new and prevalent use of self-monitoring of blood glucose, Diabetes Care, 2006;29(8):1757–63.
  22. Molnar GD, Taylor WF, Ho MM, Day-to day variations of continuously monitored glycemia: a further measure of diabetic instability, Diabetologia, 1972;8:342–8.
  23. The UK 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;352:837–53. Correction: Lancet, 1999;354:602.
  24. Sacks DB, Bruns DE, Goldstein DB, et al., Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus (Position Statement), Diabetes Care, 2002;25:750–86.
  25. Gorus F, Mathieu C, Gerlo E, How should HbA1c measurements be reported?, Diabetologia, 2006;49:7–10.
  26. Svendsen P, Lauritzen T, Soegard U, ET AL., Glycosylated haemoglobin and steady-state mean blood glucose concentration in type 1 (insulin-dependent) diabetes, Diabetologia, 1982;23:403–5.
  27. American Diabetes Association, Standards of medical care in diabetes, Diabetes Care, 2005;28:S4–36.
  28. Zhou J, Jia W, Bao Y, et al., Glycemic variability and its responses to intensive insulin treatment in newly diagnosed type 2 diabetes, Med Sci Monit, 2008;14(11):CR552–8.
  29. 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:E924–30.
  30. 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)Hoxidase activation, Diabetes, 2003;52: 2795–2804.
  31. Betteridge DJ, What is oxidative stress?, Metabolism, 2000;49(Suppl. 1):3–8.
  32. Richter C, Park JW, Ames BN, Normal oxidative damage to mitochondrial and nuclear DNA is extensive, Proc Natl Acad Sci U S A, 1988;85:6465–7.
  33. Kasai H, Crain PF, Kuchino Y, et al., Formation of 8- hydroxyguanine moiety in cellular DNA by agents producing oxygen radicals and evidence for its repair, Carcinogenesis, 1986;7:1849–51.
  34. Beckman JS, Koppenol WH, Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly, Am J Physiol, 1996;271:C1424–37.
  35. Schiekofer S, Andrassy M, Chen J, et al., Acute hyperglycemia causes intracellular formation of CML and activation of ras, p42/44 MAPK, and nuclear factor kappaB in PBMCs, Diabetes, 2003;52:621–33.
  36. DCCT Research Group, The relationship of a glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the Diabetes Control and Compllications Trial, Diabetes, 1995;44:968–83.
  37. Lachin JM, Genuth S, Nathan DM, et al., The effect of glycemic exposure on the risk of microvascular complications in the Diabetes Control and Complications Trial-revisited, Diabetes, 2008;57:995–1001.
  38. Kilpatrick ES, Rigby AS, Atkin SL, The effect of glucose variability on the risk of microvascular complications in type 1 diabetes, Diabetes Care, 2006;29(7):1486–90.
  39. Kilpatrick ES, Rigby AS, Goode K, et al., Relating mean blood glucose and glucose variability to the risk of multiple episodes of hypoglycemia in type 1 diabetes, Diabetologia, 2007;50: 2553–61.
  40. Kilpatrick ES, Rigby AS, Atkin SL, A1C variability and the risk of microvascular complications in type 1 diabetes: data from the Diabetes Control and Complications Trial, Diabetes Care, 2008;31(11):2198–2202.
  41. 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(14):1681–7.
  42. Prince C, Becker DM Costacou T, et al., Changes in glycaemic control and risk of coronary artery disease in type 1 diabetes mellitus: findings from Pittsburgh Epidemiology of Diabetes Complications Study (EDC), Diabetologia, 2007;50:2280–88.
  43. The DECODE Study Group; 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: 617–21.
  44. ADVANCE Collaborative Group, Patel A, MacMahon S, Chalmers J, et al., Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes, N Engl J Med, 2008;358: 2560–72.
  45. Duckworth W, Abraira C, Moritz T, et al.; the VADT Investigators, Intensive glucose control and complications in American veterans with type 2 diabetes, N Engl J Med, 2009;360:129–39.
  46. Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, Byington RP, et al., Effects of intensive glucose lowering in type 2 diabetes, N Engl J Med, 2008;358: 2545–59.
  47. Skyler JS, Bergenstal R, Bonow RO, et al.; American Diabetes Association; American College of Cardiology Foundation; American Heart Association, Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA diabetes trials: a position statement of the American Diabetes Association and a scientific statement of the American College of Cardiology Foundation and the American Heart Association, Diabetes Care, 2009;32:187–92.
  48. 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;321:405–12.
  49. Cryer PE, Davis SN, Shamoon H, Hypoglycemia in diabetes, Diabetes Care, 2003; 26:1902–12.
  50. Heine RJ, Van Gaal LF, Johns D, et al., for the GWAA Study Group: Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes, Ann Intern Med, 2005;143:559–69.
  51. Hirsch IB, Insulin analogues, N Engl J Med, 2005;352:174–83.
  52. Moghissi, Insulin Strategies for Managing Inpatient and Outpatient Hyperglycemia and Diabetes, Mt Sinai J Med, 2008;75:558–66.
  53. Brunelle BL, Llewelyn J, Anderson JH Jr, et al., Metaanalysis of the effect of insulin lispro on severe hypoglycemia in patients with type 1 diabetes, Diabetes Care, 1998;21:1726–31.
  54. Home PD, Lindholm A, Hylleberg B, et al., Improved glycemic control with insulin aspart: a multicenter randomized doubleblind crossover trial in type 1 diabetic patients, Diabetes Care, 1998;21:1904–9.
  55. 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 glucoselowering drugs in insulin-naïve people with type 2 diabetes, Diabetes Care, 2006;29:1269–74.
  56. 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.
  57. Riddle MC, Rosenstock J, Gerich J, on behalf of the Insulin Glargin 4002 Study Investigators, 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: 3080–86.
  58. Yki-Jarvinen H, Kauppinen-Makelin R, Tiikkainen M, et al., Insulin glargine or NPH combined with metformin in type 2 diabetes: the LANMET study, Diabetologia, 2006; 49:442–51.
  59. Brownlee M, Hirsch IB, Glycemic variability: a hemoglobin A1cindependent risk factor for diabetic complications, JAMA, 2006;295(14):1707–8.
  60. Evans JM, Newton RW, Ruta DA, et al., Frequency of blood glucose monitoring in relation to glycaemic control: observational study with diabetes database, BMJ, 1990;319:83–6.
  61. 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.
  62. Derr R, Garrett E, Stacy GA, et al., Is HbA1c affected by glycemic instability?, Diabetes Care, 2003;26:2728–33.
  63. Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group, Tamborlane WV, Beck RW, Bode BW, et al., Continuous glucose monitoring and intensive treatment of type 1 diabetes, N Engl J Med, 2008;359:1464–76.

Copyright® 2004 - 2010 Business Briefings, Ltd. All rights reserved.
Touch Endocrinology is for informational purposes and should not be considered medical advice, diagnosis or treatement recommendations.