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HbA1c Changes Against Microvascular Complications in Type 1 Diabetes

Jul 23, 2016

Does HbA1c variability predict retinopathy, nephropathy?

HbA1c changes predict microvascular complications such as retinopathy, nephropathy and cardiovascular outcomes in type 1 diabetes. The Diabetes Control and Complications Trial (DCCT) has been able to prove that rigorous therapy, which is directed at a near normal level of HbA1c, significantly reduces the risk of microvascular complications. HbA1c is the major factor of risk of complications. There was a 58% reduction in fatal and nonfatal myocardial infarctions and stroke following a rigorous treatment and the lowering of HbA1c on cardiovascular results. Patients free of complications report a good and sustained diabetes-related quality of life. Glycemic variability, possibly through an independent effect on oxidative stress, has been proposed to be an additional mediator of complications. Studies, however, have not been consistent. Fructosamine or glycated albumin are other measures of a shorter- term glycemia, also been associated with long-term complications.

The objective of this study is to investigate whether HbA1c variability contributes to the development of retinopathy, nephropathy and cardiovascular events. 1,441 subjects were enrolled in a DCCT cohort study. Qualified subjects had to be between 13-39 years, diabetes patients who have been assigned to an intensive or conventional therapy. 726 were members of the primary prevention cohort with no history of retinopathy, albumin excretion rate (AER) < 40 mg/24 h, and 1-5 years of diabetes. 715 of the remaining members were in the secondary intervention cohort with minimal to moderate non-proliferative retinopathy, AER<200 mg /24 h, and 1-5 years duration. Retinopathy severity was assessed every 6 months, AER was measured centrally from an annual 4-h timed collection. Patients were followed for an average of 6.5 years at the DCCT. Conventional groups were then instructed in intensive therapy. After that subjects were referred to their personal physicians for checkup. At the DCCT, mean HbA1c levels were 2% lower in the intensive group than in the conventional treatment group. HbA1c  was measured quarterly during the DCCT and annually during Epidemiology of Diabetes Interventions and Complications (EDIC) using a high precision, high performance liquid chromatography assay with long-term control subjects to monitor assay stability. A seven-point blood glucose profile was computed using overall mean, SD, mean amplitude of glycemic excursion, and mean of pre and postprandial values. Modification of cox proportional hazards model was used.

Glycated albumin (GA) had a marginally stronger link with measures derived from the single day blood glucose than the associations of HbA1c with glucose concentrations in all models. Mean concentration of daily blood glucose was strongly associated with HbA1c. Associations of both HbA1c and GA with mean pre-prandial, mean postprandial and the value at bedtime glucose concentrations were slightly stronger than with the overall mean. Bedtime glucose was also significant. The average X2 value was used to measure the strength of the association. The mean blood glucose (MBG) from the seven-point profile had a weaker but significant P<0.0001. For nephropathy, the link of measures of glycemia with the risk of microalbuminuria, the MBG had a weaker effect than either of the glycated products, but was not significant. When HbA1c and GA were considered together, it wasn’t significant either. For cardiovascular risk, HbA1c alone has significant P=0.027, GA was not significant alone or in combination. However, MBG alone had a significant predictor P=0.024.

HbA1c and GA individually have strong links with the progression of retinopathy both in terms of the percent changes in the factor and the model X2 value. The strongest association with retinopathy was observed when GA and HbA1c were included at 0.05 level. Both retinopathy and nephropathy connection with MBG were significantly weaker. Variability of HbA1c levels over time that were measured, that is over 6 years, proposed an independent risk factor for nephropathy and cardiovascular events. HbA1c had major links with CVD outcomes as well as MBG, but not between GA with CVD. There was no index of chronic glycemia having significant relationship with CVD. This is because retinopathy and nephropathy are more specific to diabetes than to CVD. Some of the weaknesses of this study include the dependence on seven-point glucose profile measured quarterly, but measured annually to capture MBG concentrations and variability over time. Also the profiles only rely on the subject collection, which was a potential source of error. In conclusion, both HbA1c and GA were linked to microvascular complications, but only HbA1c was associated with cardiovascular complications.

Practice Pearls:

  • Chronic glycemia is a major modifiable factor driving the development and progression of the complications of type 1 diabetes.
  • With intensive management of diabetes, patients can achieve lower glycemia and reduce the risk of developing microvascular complications such as retinopathy, nephropathy and risk in cardiovascular outcomes
  • Both HbA1c and GA were similarly linked to microvascular complications but only HbA1c was associated with cardiovascular complications.


Gubitosi-Klug, Rose A., and for the DCCT/EDIC Research Group. “The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study at 30 Years: Summary and Future Directions.” Diabetes Care 37.1 (2014): 44–49. PMC. Web. 29 June 2016.

Nathan, David M. et al. “Relationship of Glycated Albumin to Blood Glucose and HbA1c Values and to Retinopathy, Nephropathy, and Cardiovascular Outcomes in the DCCT/EDIC Study.” Diabetes 63.1 (2014): 282–290. PMC. Web. 29 June 2016.

The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. “Retinopathy and Nephropathy in Patients with Type 1 Diabetes Four Years after A Trial of Intensive Therapy.” The New England journal of medicine 342.6 (2000): 381–389. Print.