Glycated hemoglobin variability and retinopathy progression in type 1 diabetes: Is month-to-moth instability a better predictor?

Glucose instability has been proposed to be one of the risk factors for diabetic complications, in particular retinopathy, since the publication of the Diabetes Control and Complication Trial (DCCT) 20 years ago. In that study, as compared with conventional therapy, intensive therapy effectively delays the onset and slows the progression of diabetic complications in patients with type 1 diabetes1. The following analyses have found that in addition to mean glycated hemoglobin (HbA1c) level, high HbA1c variability, but not glucose variability, might be associated with increased risks of retinopathy, nephropathy and perhaps neuropathy, in type 1 diabetic patients (Table 1)2. Although many laboratory and clinical studies suggested that ‘short‐term’ glucose fluctuation, mostly driven by high postprandial blood glucose levels, leading to increased oxidative stress and decreased endothelial function, is responsible for the higher risks of microvascular and cardiovascular outcomes in type 2 diabetic patients9, the role of ‘longer‐term’ glucose stability in terms of HbA1c variability, and the occurrence and progression of diabetic complications among type 1 diabetic patients remains elusive.

Table 1

Studies examining the relationship between glucose or glycated hemoglobin variability and long‐term complications in type 1 diabetic patients

Author, year	Data source	No. participants	Follow‐up duration	Variability measurement	Outcome	Results
Kilpatrick, 20062	DCCT	1,441	5 years	Seven‐point glucose profiles were collected quarterly. The mean area under the curve and the SD of glucose variability within‐day and between visits were calculated	Retinopathy Nephropathy	Within‐day and between‐day glucose variability does not appear to be an additional factor in the development or progression of either retinopathy nor nephropathy
Kilpatrick, 20083	DCCT	1,441	NR	HbA1c was collected quarterly. The mean HbA1c and the SD of HbA1c variability from 6 months onwards were calculated	Retinopathy Nephropathy	A1c variability added to mean A1c in predicting the risk of development or progression of retinopathy (HR 2.26 for every 1% increase in HbA1c SD [95% CI 1.63–3.14]) and nephropathy (HR 1.80 [95% CI 1.37–2.42])
Bragd, 20084	Outpatient clinic at one hospital	100	11 years	SD of blood glucose was calculated based on 70 measurements over 4 weeks	Retinopathy Nephropathy Neuropathy	Glucose variability was significantly related to the presence of peripheral neuropathy (OR 2.34 [96% CI 1.06–5.20]), but not with incidence of proliferative retinopathy (HR 1.37 [95% CI 0.77–2.43]) nor nephropathy (HR 1.75 [95% CI 0.89–3.40])
Kilpatrick, 20095	DCCT EDIC (first 4 years)	1,441	NR	Mean area under the curve glucose and the within‐day glucose variability (SD and MAGE) during the DCCT	Retinopathy Nephropathy	Glucose variability in the DCCT did not predict the development of retinopathy or nephropathy by EDIC year 4
Siegelaar, 20096	DCCT	1,160	5 years	Variability of blood glucose (within‐day SD) was calculated as the SD of daily blood glocose around the mean from each quarterly visit and MAGE	Neuropathy	No effect of glucose variability on confirmed clinical neuropathy, autonomic neuropathy and abnormal nerve conduction
Waden, 20097	FinnDiane	2,107	5.7 years	SD of all recorded A1c	Incident microalbuminuria, renal disease progression, cardiovascular event (MI, stroke, CABG, PTCA, limb ampuation)	SD of serial A1c was independently associated with progression of renal disease (HR 1.92 [95% CI 1.49–2.47]) and of a cardiovascular event (HR 1.98 [95% CI 1.39–2.82])
Marcovecchio, 20118	ORPS NFS	1,232	NR	For each patient, the intrapersonal SD for annual HbA1c was calculated	Microalbuminuria development	HbA1c SD was independently associated with microalbuminuria (HR 1.31 for every 1% increase in HbA1c SD [95% CI 1.01‐1.35])
Hietala, 201310	FinnDiane	2,019	5.2 years	Coeffecient of variation (the ratio of intrapersonal SD and mean) of HbA1c	Retinopathy	HbA1c variability was associated with an increased risk of retinopathy requiring laser treatment (HR 1.60 [95% CI 1.10–2.50] comparing the highest with the lowest quartile)

CABG, coronary artery bypass graft surgery; CI, confidence interval; DCCT, Diabetes Control and Complication Trial; EDIC, Epidemiology of Diabetes Interventions and Complications; HbA1c, glycated hemoglobin; HR, hazard ratio; MAGE, mean amplitude of glycemic excursions; MI, myocardial infarction; NR, not reported; OR, odds ratio; PTCA, percutaneous transluminal coronary angioplasty; SD, standard deviation.

In a recently published study, Hietala et al.10 analyzed data from 2,019 type 1 diabetic patients who were enrolled in the Finnish Diabetic Nephropathy (FinnDiane) study. During the average follow up of 5.2 years, they have reconfirmed that high HbA1c variability was associated with an increased risk of incidence, as well as laser treatment for retinopathy. In the earlier report, they also showed that HbA1c variability was not only predictive of incident microalbuminuria and progression of renal disease, but also of incident cardiovascular events in type 1 diabetic patients7. Of note, patients with high mean HbA1c values also had high HbA1c variability. However, patients with low mean HbA1c value, but high HbA1c variability, had similar incidence for nephropathy progression as patients with high mean HbA1c value, but low HbA1c variability, suggesting an equally important effect of both absolute value and stability in the risk of progression in renal outcome. The significant association between HbA1c variability, and risks of retinopathy and nephropathy persisted even after taking the number of HbA1c measurements into consideration.

Why was HbA1c instability independently associated with a higher chance of laser treatment for retinopathy? The authors emphasized that even short periods of higher HbA1c could have a sustained effect on worsening of retinopathy despite subsequent improvement in glycemic control10. However, because of the inherent limitations in the observational study design, there might be other explanations for the observed association (Figure 1). First, because there might be a lag time between worsening of visual symptoms and laser treatment, it is possible that diagnosis of retinopathy progression per se leads to attempts to improve glycemic control by physicians, and hence increasing HbA1c fluctuation (protopathic bias or reverse causation). Second, for poorly controlled patients with high and unstable HbA1c value, physicians were more likely to do fundoscopic or fundus photographic examinations, and were hence more likely to find retinopathy progression that might require laser treatment (detection bias). Third, from prior studies we knew that a variable HbA1c profile is associated with several factors, such as low socioeconomic status, physical inactivity and smoking7. Perhaps, it is these lifestyle and behavior factors (including medication non‐adherence) that lead to poor outcomes.

Figure 1

Possible explanations for the observed positive association between glycated hemoglobin (HbA1c) variability and retinopathy among type 1 diabetic patients.

Again, we want to reassure our patients that long‐term optimal glycemic control is crucial to reduce retinopathy occurrence and its complications. For healthcare professionals who are involved in the care of diabetic patients, the findings of the study by Hietala et al.10 highlight that patients with highly variable HbA1c warrant careful monitoring of retinopathy development and progression. Further research on the mechanism of the observed association and how to prevent early retinopathy worsening for those poorly controlled type 1 patients undergoing intensive glucose lowering therapy are required to fill the knowledge gap.