Diabetes Metab J.  2018 Dec;42(6):496-512. 10.4093/dmj.2018.0026.

Cardiovascular Autonomic Neuropathy Predicts Higher HbA1c Variability in Subjects with Type 2 Diabetes Mellitus

• Yang Y
• Lee EY
• Cho JH
• Park YM
• Ko SH
• Yoon KH
• Kang MI
• Cha BY
• Lee SH

• KMID: 2449627
• DOI: http://doi.org/10.4093/dmj.2018.0026

Abstract

BACKGROUND
This study aimed to investigate the association between the presence and severity of cardiovascular autonomic neuropathy (CAN) and development of long-term glucose fluctuation in subjects with type 2 diabetes mellitus.
METHODS
In this retrospective cohort study, subjects with type 2 diabetes mellitus who received cardiovascular autonomic reflex tests (CARTs) at baseline and at least 4-year of follow-up with ≥6 measures of glycosylated hemoglobin (HbA1c) were included. The severity of CAN was categorized as normal, early, or severe CAN according to the CARTs score. HbA1c variability was measured as the standard deviation (SD), coefficient of variation, and adjusted SD of serial HbA1c measurements.
RESULTS
A total of 681 subjects were analyzed (294 normal, 318 early, and 69 severe CAN). The HbA1c variability index values showed a positive relationship with the severity of CAN. Multivariable logistic regression analysis showed that CAN was significantly associated with the risk of developing higher HbA1c variability (SD) after adjusting for age, sex, body mass index, diabetes duration, mean HbA1c, heart rate, glomerular filtration rate, diabetic retinopathy, coronary artery disease, insulin use, and anti-hypertensive medication (early CAN: odds ratio [OR], 1.65; 95% confidence interval [CI], 1.12 to 2.43) (severe CAN: OR, 2.86; 95% CI, 1.47 to 5.56). This association was more prominent in subjects who had a longer duration of diabetes (>10 years) and lower mean HbA1c ( < 7%).
CONCLUSION
CAN is an independent risk factor for future higher HbA1c variability in subjects with type 2 diabetes mellitus. Tailored therapy for stabilizing glucose fluctuation should be emphasized in subjects with CAN.

Keyword

Biological variation, individual; Diabetes mellitus, type 2; Diabetic neuropathies; Glycated hemoglobin A

MeSH Terms

Body Mass Index
Cohort Studies
Coronary Artery Disease
Diabetes Mellitus, Type 2*
Diabetic Neuropathies
Diabetic Retinopathy
Follow-Up Studies
Glomerular Filtration Rate
Glucose
Heart Rate
Hemoglobin A, Glycosylated
Insulin
Logistic Models
Odds Ratio
Reflex
Retrospective Studies
Risk Factors
Glucose
Insulin

Figure

• 

  Fig. 1 Future glycosylated hemoglobin (HbA1c) variability indices according to baseline cardiovascular autonomic neuropathy (CAN) severity. (A) The value of each HbA1c variability index according to the severity of CAN at baseline. (B) The percentage of the higher HbA1c variability group according to the severity of CAN at baseline. Data are expressed as the mean±standard deviation (SD). CV, coefficient of variation; Adj, adjusted. aP<0.05.

Reference

1. Vinik AI, Ziegler D. Diabetic cardiovascular autonomic neuropathy. Circulation. 2007; 115:387–397. PMID: 17242296.

2. Maser RE, Mitchell BD, Vinik AI, Freeman R. The association between cardiovascular autonomic neuropathy and mortality in individuals with diabetes: a meta-analysis. Diabetes Care. 2003; 26:1895–1901. PMID: 12766130.

3. Spallone V, Ziegler D, Freeman R, Bernardi L, Frontoni S, Pop-Busui R, Stevens M, Kempler P, Hilsted J, Tesfaye S, Low P, Valensi P. Toronto Consensus Panel on Diabetic Neuropathy. Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management. Diabetes Metab Res Rev. 2011; 27:639–653. PMID: 21695768.

4. Stephenson JM, Kempler P, Perin PC, Fuller JH. Is autonomic neuropathy a risk factor for severe hypoglycaemia? The EURODIAB IDDM Complications Study. Diabetologia. 1996; 39:1372–1376. PMID: 8933007.

5. Meyer C, Grossmann R, Mitrakou A, Mahler R, Veneman T, Gerich J, Bretzel RG. Effects of autonomic neuropathy on counterregulation and awareness of hypoglycemia in type 1 diabetic patients. Diabetes Care. 1998; 21:1960–1966. PMID: 9802751.

6. Yun JS, Kim JH, Song KH, Ahn YB, Yoon KH, Yoo KD, Park YM, Ko SH. Cardiovascular autonomic dysfunction predicts severe hypoglycemia in patients with type 2 diabetes: a 10-year follow-up study. Diabetes Care. 2014; 37:235–241. PMID: 23959567.

7. Bottini P, Boschetti E, Pampanelli S, Ciofetta M, Del Sindaco P, Scionti L, Brunetti P, Bolli GB. Contribution of autonomic neuropathy to reduced plasma adrenaline responses to hypoglycemia in IDDM: evidence for a nonselective defect. Diabetes. 1997; 46:814–823. PMID: 9133549.

8. Gorst C, Kwok CS, Aslam S, Buchan I, Kontopantelis E, Myint PK, Heatlie G, Loke Y, Rutter MK, Mamas MA. Long-term glycemic variability and risk of adverse outcomes: a systematic review and meta-analysis. Diabetes Care. 2015; 38:2354–2369. PMID: 26604281.

9. 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. PMID: 18650371.

10. Suh S, Kim JH. Glycemic variability: how do we measure it and why is it important? Diabetes Metab J. 2015; 39:273–282. PMID: 26301188.

11. 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. PMID: 19651819.

12. Hsu CC, Chang HY, Huang MC, Hwang SJ, Yang YC, Lee YS, Shin SJ, Tai TY. HbA1c variability is associated with microal buminuria development in type 2 diabetes: a 7-year prospective cohort study. Diabetologia. 2012; 55:3163–3172. PMID: 22923064.

13. Penno G, Solini A, Bonora E, Fondelli C, Orsi E, Zerbini G, Morano S, Cavalot F, Lamacchia O, Laviola L, Nicolucci A, Pugliese G. Renal Insufficiency And Cardiovascular Events Study Group. HbA1c variability as an independent correlate of nephropathy, but not retinopathy, in patients with type 2 diabetes: the Renal Insufficiency And Cardiovascular Events (RIACE) Italian multicenter study. Diabetes Care. 2013; 36:2301–2310. PMID: 23491522.

14. Prince CT, Becker DJ, Costacou T, Miller RG, Orchard TJ. Changes in glycaemic control and risk of coronary artery disease in type 1 diabetes: findings from the Pittsburgh Epidemiology of Diabetes Complications Study (EDC). Diabetologia. 2007; 50:2280–2288. PMID: 17768606.

15. Hirakawa Y, Arima H, Zoungas S, Ninomiya T, Cooper M, Hamet P, Mancia G, Poulter N, Harrap S, Woodward M, Chalmers J. Impact of visit-to-visit glycemic variability on the risks of macrovascular and microvascular events and all-cause mortality in type 2 diabetes: the ADVANCE trial. Diabetes Care. 2014; 37:2359–2365. PMID: 24812434.

16. Lee EJ, Kim YJ, Kim TN, Kim TI, Lee WK, Kim MK, Park JH, Rhee BD. A1c variability can predict coronary artery disease in patients with type 2 diabetes with mean a1c levels greater than 7. Endocrinol Metab (Seoul). 2013; 28:125–132. PMID: 24396666.

17. 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. PMID: 10938048.

18. Currie CJ, Peters JR, Tynan A, Evans M, Heine RJ, Bracco OL, Zagar T, Poole CD. Survival as a function of HbA(1c) in people with type 2 diabetes: a retrospective cohort study. Lancet. 2010; 375:481–489. PMID: 20110121.

19. Ewing DJ, Martyn CN, Young RJ, Clarke BF. The value of cardiovascular autonomic function tests: 10 years experience in diabetes. Diabetes Care. 1985; 8:491–498. PMID: 4053936.

20. Bellavere F, Bosello G, Fedele D, Cardone C, Ferri M. Diagnosis and management of diabetic autonomic neuropathy. Br Med J (Clin Res Ed). 1983; 287:61.

21. Boulton AJ, Vinik AI, Arezzo JC, Bril V, Feldman EL, Freeman R, Malik RA, Maser RE, Sosenko JM, Ziegler D. American Diabetes Association. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care. 2005; 28:956–962. PMID: 15793206.

22. Tesfaye S, Boulton AJ, Dyck PJ, Freeman R, Horowitz M, Kempler P, Lauria G, Malik RA, Spallone V, Vinik A, Bernardi L, Valensi P. Toronto Diabetic Neuropathy Expert Group. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care. 2010; 33:2285–2293. PMID: 20876709.

23. Niijima A. Nervous regulation of metabolism. Prog Neurobiol. 1989; 33:135–147. PMID: 2678269.

24. Lehmann R, Borovicka J, Kunz P, Crelier G, Boesiger P, Fried M, Schwizer W, Spinas GA. Evaluation of delayed gastric emptying in diabetic patients with autonomic neuropathy by a new magnetic resonance imaging technique and radio-opaque markers. Diabetes Care. 1996; 19:1075–1082. PMID: 8886552.

25. Darwiche G, Almer LO, Bjorgell O, Cederholm C, Nilsson P. Delayed gastric emptying rate in type 1 diabetics with cardiac autonomic neuropathy. J Diabetes Complications. 2001; 15:128–134. PMID: 11358681.

26. Ohlsson B, Melander O, Thorsson O, Olsson R, Ekberg O, Sundkvist G. Oesophageal dysmotility, delayed gastric emptying and autonomic neuropathy correlate to disturbed glucose homeostasis. Diabetologia. 2006; 49:2010–2014. PMID: 16832660.

27. Parthasarathy G, Kudva YC, Low PA, Camilleri M, Basu A, Bharucha AE. Relationship between gastric emptying and diurnal glycemic control in type 1 diabetes mellitus: a randomized trial. J Clin Endocrinol Metab. 2017; 102:398–406. PMID: 27880079.

28. Jones KL, Horowitz M, Carney BI, Wishart JM, Guha S, Green L. Gastric emptying in early noninsulin-dependent diabetes mellitus. J Nucl Med. 1996; 37:1643–1648. PMID: 8862300.

29. Hongo M, Okuno Y. Diabetic gastropathy in patients with autonomic neuropathy. Diabet Med. 1993; 10(Suppl 2):79S–81S. PMID: 8334850.

30. Lyrenas EB, Olsson EH, Arvidsson UC, Orn TJ, Spjuth JH. Prevalence and determinants of solid and liquid gastric emptying in unstable type I diabetes. Relationship to postprandial blood glucose concentrations. Diabetes Care. 1997; 20:413–418. PMID: 9051396.

31. Penno G, Solini A, Zoppini G, Orsi E, Fondelli C, Zerbini G, Morano S, Cavalot F, Lamacchia O, Trevisan R, Vedovato M, Pugliese G. Renal Insufficiency and Cardiovascular Events (RIACE) Study Group. Hemoglobin A1c variability as an independent correlate of cardiovascular disease in patients with type 2 diabetes: a cross-sectional analysis of the Renal Insufficiency And Cardiovascular Events (RIACE) Italian multicenter study. Cardiovasc Diabetol. 2013; 12:98. PMID: 23829205.

32. Clark MG, Wallis MG, Barrett EJ, Vincent MA, Richards SM, Clerk LH, Rattigan S. Blood flow and muscle metabolism: a focus on insulin action. Am J Physiol Endocrinol Metab. 2003; 284:E241–E258. PMID: 12531739.

33. Clark MG. Impaired microvascular perfusion: a consequence of vascular dysfunction and a potential cause of insulin resistance in muscle. Am J Physiol Endocrinol Metab. 2008; 295:E732–E750. PMID: 18612041.

34. Prentki M, Nolan CJ. Islet beta cell failure in type 2 diabetes. J Clin Invest. 2006; 116:1802–1812. PMID: 16823478.

35. Jun JE, Jin SM, Baek J, Oh S, Hur KY, Lee MS, Lee MK, Kim JH. The association between glycemic variability and diabetic cardiovascular autonomic neuropathy in patients with type 2 diabetes. Cardiovasc Diabetol. 2015; 14:70. PMID: 26041130.

36. Spallone V, Bellavere F, Scionti L, Maule S, Quadri R, Bax G, Melga P, Viviani GL, Esposito K, Morganti R, Cortelli P. Diabetic Neuropathy Study Group of the Italian Society of Diabetology. Recommendations for the use of cardiovascular tests in diagnosing diabetic autonomic neuropathy. Nutr Metab Cardiovasc Dis. 2011; 21:69–78. PMID: 21247746.

37. Assessment: clinical autonomic testing report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 1996; 46:873–880. PMID: 8618715.