Endocrinol Metab.  2013 Jun;28(2):125-132. 10.3803/EnM.2013.28.2.125.

A1c Variability Can Predict Coronary Artery Disease in Patients with Type 2 Diabetes with Mean A1c Levels Greater than 7

• Lee EJ
• Kim YJ
• Kim TN
• Kim TI
• Lee WK
• Kim MK
• Park JH
• Rhee BD

• KMID: 1973811
• DOI: http://doi.org/10.3803/EnM.2013.28.2.125

Abstract

BACKGROUND
Recent studies suggested that the association of acute glucose variability and diabetic complications was not consistent, and that A1c variability representing long term glucose fluctuation may be related to coronary atherosclerosis in patients with type 1 diabetes. In this study, we attempt to determine whether or not A1c variability can predict coronary artery disease (CAD) in patients with type 2 diabetes.
METHODS
We reviewed data of patients with type 2 diabetes who had undergone coronary angiography (CAG) and had been followed up with for 5 years. The intrapersonal standard deviation (SD) of serially-measured A1c levels adjusted by the different number of assessments among patients (adj-A1c-SD) was considered to be a measure of the variability of A1c.
RESULTS
Among the 269 patients, 121 of them had type 2 diabetes with CAD. In patients with A1c > or =7%, the mean A1c levels and A1c levels at the time of CAG among the three groups were significantly different. The ratio of patients with CAD was the highest in the high adj-A1c-SD group and the lowest in the low adj-A1c-SD group (P=0.017). In multiple regression analysis, adj-A1c-SD was an independent predictor for CAD in subjects with A1c > or =7% (odds ratio, 2.140; P=0.036).
CONCLUSION
Patients with higher A1c variability for several years showed higher mean A1c levels. A1c variability can be an independent predictor for CAD as seen in angiographs of patients with type 2 diabetes with mean A1c levels over 7%.

Keyword

A1c variability; Coronary artery disease; Diabetes mellitus, type 2

MeSH Terms

Coronary Angiography
Coronary Artery Disease
Coronary Vessels
Diabetes Complications
Diabetes Mellitus, Type 2
Glucose
Humans
Glucose

Figure

• 

  Fig. 1 The percentage of patients with A1c <7% and ≥7% in groups divided by tertile of adjusted standard deviation (SD) of serial A1c levels (chi-square, P<0.001).

Reference

1. Klein R. Hyperglycemia and microvascular and macrovascular disease in diabetes. Diabetes Care. 1995. 18:258–268.

2. Turner RC, Millns H, Neil HA, Stratton IM, Manley SE, Matthews DR, Holman RR. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23). BMJ. 1998. 316:823–828.

3. Kuusisto J, Mykkanen L, Pyorala K, Laakso M. NIDDM and its metabolic control predict coronary heart disease in elderly subjects. Diabetes. 1994. 43:960–967.

4. The 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.

5. Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, Hadden D, Turner RC, Holman RR. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000. 321:405–412.

6. Clark CM Jr, Perry RC. Type 2 diabetes and macrovascular disease: epidemiology and etiology. Am Heart J. 1999. 138(5 Pt 1):S330–S333.

7. Eastman RC, Javitt JC, Herman WH, Dasbach EJ, Copley-Merriman C, Maier W, Dong F, Manninen D, Zbrozek AS, Kotsanos J, Garfield SA, Harris M. Model of complications of NIDDM. II. Analysis of the health benefits and cost-effectiveness of treating NIDDM with the goal of normoglycemia. Diabetes Care. 1997. 20:735–744.

8. Eastman RC, Javitt JC, Herman WH, Dasbach EJ, Zbrozek AS, Dong F, Manninen D, Garfield SA, Copley-Merriman C, Maier W, Eastman JF, Kotsanos J, Cowie CC, Harris M. Model of complications of NIDDM. I. Model construction and assumptions. Diabetes Care. 1997. 20:725–734.

9. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003. 348:383–393.

10. The relationship of glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the diabetes control and complications trial. Diabetes. 1995. 44:968–983.

11. Brownlee M, Hirsch IB. Glycemic variability: a hemoglobin A1c-independent risk factor for diabetic complications. JAMA. 2006. 295:1707–1708.

12. Waden J, Forsblom C, Thorn LM, Gordin D, Saraheimo M, Groop PH. Finnish Diabetic Nephropathy Study Group. A1C variability predicts incident cardiovascular events, microalbuminuria, and overt diabetic nephropathy in patients with type 1 diabetes. Diabetes. 2009. 58:2649–2655.

13. Quagliaro L, Piconi L, Assaloni R, Martinelli L, Motz E, Ceriello A. 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.

14. Risso A, Mercuri F, Quagliaro L, Damante G, Ceriello A. Intermittent high glucose enhances apoptosis in human umbilical vein endothelial cells in culture. Am J Physiol Endocrinol Metab. 2001. 281:E924–E930.

15. Jones SC, Saunders HJ, Qi W, Pollock CA. Intermittent high glucose enhances cell growth and collagen synthesis in cultured human tubulointerstitial cells. Diabetologia. 1999. 42:1113–1119.

16. Kim M, Chung H, Yoon C, Lee E, Kim T, Kwon M, Lee S, Rhee B, Park J. Increase of INS-1 cell apoptosis under glucose fluctuation and the involvement of FOXO-SIRT pathway. Diabetes Res Clin Pract. 2012. 98:132–139.

17. Su G, Mi S, Tao H, Li Z, Yang H, Zheng H, Zhou Y, Ma C. Association of glycemic variability and the presence and severity of coronary artery disease in patients with type 2 diabetes. Cardiovasc Diabetol. 2011. 10:19.

18. Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999. 340:115–126.

19. Kilpatrick ES, Rigby AS, Atkin SL. The effect of glucose variability on the risk of microvascular complications in type 1 diabetes. Diabetes Care. 2006. 29:1486–1490.

20. 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. 31:2198–2202.

21. Muggeo M, Zoppini G, Bonora E, Brun E, Bonadonna RC, Moghetti P, Verlato G. Fasting plasma glucose variability predicts 10-year survival of type 2 diabetic patients: the Verona Diabetes Study. Diabetes Care. 2000. 23:45–50.

22. Watada H, Azuma K, Kawamori R. Glucose fluctuation on the progression of diabetic macroangiopathy: new findings from monocyte adhesion to endothelial cells. Diabetes Res Clin Pract. 2007. 77:Suppl 1. S58–S61.

23. Otsuka A, Azuma K, Iesaki T, Sato F, Hirose T, Shimizu T, Tanaka Y, Daida H, Kawamori R, Watada H. Temporary hyperglycaemia provokes monocyte adhesion to endothelial cells in rat thoracic aorta. Diabetologia. 2005. 48:2667–2674.

24. Azuma K, Kawamori R, Toyofuku Y, Kitahara Y, Sato F, Shimizu T, Miura K, Mine T, Tanaka Y, Mitsumata M, Watada H. Repetitive fluctuations in blood glucose enhance monocyte adhesion to the endothelium of rat thoracic aorta. Arterioscler Thromb Vasc Biol. 2006. 26:2275–2280.

25. Ceriello A. The emerging role of post-prandial hyperglycaemic spikes in the pathogenesis of diabetic complications. Diabet Med. 1998. 15:188–193.

26. Hodgkinson CP, Laxton RC, Patel K, Ye S. Advanced glycation end-product of low density lipoprotein activates the toll-like 4 receptor pathway implications for diabetic atherosclerosis. Arterioscler Thromb Vasc Biol. 2008. 28:2275–2281.

27. Toth E, Racz A, Toth J, Kaminski PM, Wolin MS, Bagi Z, Koller A. Contribution of polyol pathway to arteriolar dysfunction in hyperglycemia. Role of oxidative stress, reduced NO, and enhanced PGH(2)/TXA(2) mediation. Am J Physiol Heart Circ Physiol. 2007. 293:H3096–H3104.

28. Geraldes P, King GL. Activation of protein kinase C isoforms and its impact on diabetic complications. Circ Res. 2010. 106:1319–1331.

29. Ge QM, Dong Y, Zhang HM, Su Q. Effects of intermittent high glucose on oxidative stress in endothelial cells. Acta Diabetol. 2010. 47:Suppl 1. 97–103.

30. Quagliaro L, Piconi L, Assaloni R, Da Ros R, Maier A, Zuodar G, Ceriello A. Intermittent high glucose enhances ICAM-1, VCAM-1 and E-selectin expression in human umbilical vein endothelial cells in culture: the distinct role of protein kinase C and mitochondrial superoxide production. Atherosclerosis. 2005. 183:259–267.

31. Monnier L, Mas E, Ginet C, Michel F, Villon L, Cristol JP, Colette C. Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes. JAMA. 2006. 295:1681–1687.

32. Action to Control Cardiovascular Risk in Diabetes Study Group. Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse JB, Cushman WC, Genuth S, Ismail-Beigi F, Grimm RH Jr, Probstfield JL, Simons-Morton DG, Friedewald WT. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008. 358:2545–2559.

33. ADVANCE Collaborative Group. Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, Marre M, Cooper M, Glasziou P, Grobbee D, Hamet P, Harrap S, Heller S, Liu L, Mancia G, Mogensen CE, Pan C, Poulter N, Rodgers A, Williams B, Bompoint S, de Galan BE, Joshi R, Travert F. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008. 358:2560–2572.

34. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, Zieve FJ, Marks J, Davis SN, Hayward R, Warren SR, Goldman S, McCarren M, Vitek ME, Henderson WG, Huang GD. VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009. 360:129–139.

35. Zoungas S, Chalmers J, Ninomiya T, Li Q, Cooper ME, Colagiuri S, Fulcher G, de Galan BE, Harrap S, Hamet P, Heller S, MacMahon S, Marre M, Poulter N, Travert F, Patel A, Neal B, Woodward M. ADVANCE Collaborative Group. Association of HbA1c levels with vascular complications and death in patients with type 2 diabetes: evidence of glycaemic thresholds. Diabetologia. 2012. 55:636–643.