The Association Between Glycemic Variability and Diabetic Cardiovascular Autonomic Neuropathy in Patients With Type 2 Diabetes

Ji Eun Jun; Sang-Man Jin; Jongha Baek; Sewon Oh; Kyu Yeon Hur; Myung-Shik Lee; Moon-Kyu Lee; Jae Hyeon Kim


Cardiovasc Diabetol. 2015;14(70) 

In This Article


Diabetic cardiovascular autonomic neuropathy (CAN) is one of several common diabetic microvascular complications. CAN involves autonomic nerve fibers innervating the heart and blood vessels, and consequentially represents a significant cause of cardiovascular morbidity and mortality in diabetic patients.[1] A growing body of clinical and laboratory evidence suggests that glycemic variability (GV) may play a role in developing autonomic neuropathy independently of chronic hyperglycemia, by contributing to oxidative stress that leads to neural damage.[2,3] Nevertheless, there has been considerable debate over whether glycemic instability confers a risk of diabetic complications in addition to that predicted by mean glycemia alone.[4]

Glycemic variability refers to short-term fluctuations in glycemia, such as within-day variability, variability between daily means, or within-series variability.[5] Early post-hoc analysis of data from the Diabetes Control and Complications Trial (DCCT) using seven-point self-monitoring blood glucose (SMBG) levels revealed no significant association between short-term GV and diabetic retinopathy, nephropathy,[6] or neuropathy, which was defined as abnormal nerve conduction, sensory signs, and heart rate variability in type 1 diabetes.[7] The Epidemiology of Diabetes Interventions and Complications (EDIC) study, which was extended from the DCCT, also found no evidence of a contribution of short-term GV to retinopathy or nephropathy.[8] However, one of the limitations in those studies was that the seven-point glucose profiles did not adequately reflect overall glycemic patterns.

Continuous glucose monitoring (CGM) is now regarded as a more accurate method for the assessment of glycemic variability than is SMBG.[9] Several studies[10,11] have in fact demonstrated that increased short-term GV was associated with diabetic microvascular complications, by using CGM data.

Whereas CGM measures short-term fluctuation of glycemia, HbA1c variability reflects glycemic fluctuation over longer periods of time, as HbA1c reflects glycemic control over 2–3 months.[12] Two large trials[13,14] reported that duration of diabetes, not SD of HbA1c, was an independent risk factor for diabetic retinopathy, whereas a subcohort analysis from a Finnish Diabetic Nephropathy (FinnDiane) study[15] reported that higher HbA1c variability (CV of HbA1c) was associated with an increased need for laser treatment in patients with type 1 diabetes. Microalbuminuria or CKD stage was more concordantly related to HbA1c variability independent of mean HbA1c in patients with type 2 diabetes.[13,16,17] Diabetic nephropathy is known as the most sensitive complication to changes in HbA1c.[18]

Because the majority of studies regarding the effect of GV on diabetic microvascular complications have focused on retinopathy or nephropathy, little is known whether GV is associated with diabetic autonomic neuropathy, and in particularly with CAN. Thus far, one cross-sectional study[19] showed that heart rate variability, one of the earliest indicators of CAN, significantly correlated with GV (SD of mean glucose, M-value) measured by CGM in patients with type 2 diabetes. An additional small study[20] showed that MAGE calculated from CGM data affected sympathovagal balance in 26 type 2 diabetic patients without overt autonomic neuropathy. However, we have found no previous study on the influence of HbA1c variability on CAN.

The aim of this study was therefore to determine whether short-term GV measured by three-day CGM or HbA1c variability is associated with the presence and severity of CAN.