The Effect of HbA1c Variability on Cardiovascular Disease

The new HbA1c variability score (HVS) allows HbA1c variability to be more easily and consistently studied.    

Lowering blood glucose is, of course, important; so is how glucose is lowered. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study was terminated early due to increased mortality. The authors of this study interpret this as meaning that normalization of blood glucose levels should not be the only target of diabetes treatment. They believe that glycemic variability may be a factor that could be used to explain differences in cardiovascular outcomes between studies. Glycemic variability can be either glucose fluctuation during the day or over a long-term period, with the latter being more studied. Most of those studies evaluated HbA1c variability using the standard deviation or coefficient of variation. Those studies suggested an association with all-cause mortality. Recently, a new scale, the HbA1c variability score (HVS), was developed to allow HbA1c variability to be more easily and consistently studied. HVS is the number of measures where HbA1c changed by >0.5% from the previous value, as a percentage of the total number of HbA1c measures. This new scale is what this study used to evaluate variability.  

The authors of this study wanted to investigate the association between HbA1c variability and cardiovascular diseases as well as a microvascular complication in a large population. This retrospective cohort study included 13,111-19,883 patients using the Scottish electronic health record system. Patients had to be over 40 years when they were diagnosed with type 2 diabetes and had their first HbA1c measurement within one year of diagnosis of diabetes, with a total of at least 5 HbA1c measurements. Patients were excluded if their data was incomplete. The study looked at ten different outcomes: Major adverse cardiovascular events; all-cause mortality; atherosclerotic cardiovascular (ASCV) death; hospitalization or death from coronary artery disease, ischemic stroke, or heart failure; observable background diabetic retinopathy; diabetic peripheral neuropathy; diabetic foot ulcer (DFU); and the new onset of chronic kidney disease (CKD). If any of these occurred within three years of diagnosis, the participant was excluded, as there would not be enough time to define the HbA1c variability score and the outcomes would have been unlikely to be related to the HVS. At baseline, 21,352 patients were analyzed, with a median follow-up of 6.8 years and a mean HbA1c of 7.7% ± 2%.   

Using the group with an HVS category of 0-20 as a control, patients with an HVS of >60 were at an increased risk of all outcomes. Those with an HVS of >80 to ≤ 100 had an increased risk of: major adverse cardiovascular event (HR 2.38 [95% CI 1.61-3.53]), all-cause mortality (2.4 [1.72-3.33]), coronary artery disease (2.63 [1.81-3.84]), ischemic stroke (2.04 [1.12-3.73]), heart failure (3.23 [1.76-5.93]), diabetic peripheral neuropathy (3.07 [2.23-4.22]), DFU (5.24 [2.61-10.49]), and CKD (3.49 [2.47-4.95]). The increased risks of the ten outcomes were all statistically significant (P = 0.023 or less) in those with an HVS of over 60. Of the participants that had an HVS of >40 but ≤60, only the increased risk of ischemic stroke was not statistically significant (P = 0.439). Of those with an HVS of >20 but ≤40, only ischemic stroke (P = 0.025) and diabetic peripheral neuropathy (P = 0.02) were statistically significant. Participants that had an HbA1c of <7% saw a stronger association between HVS and coronary artery disease, ischemic stroke, and progression to CKD. Subgroup analysis that looked at age, sex, obesity at baseline, and treatment at baseline did not show significant differences in the trend of the association.   

This may be the first population-based study that investigated the association of HbA1c variability and comprehensive endpoints in patients with newly diagnosed type 2 diabetes. The highest elevation risk was seen in those with an HVS of >60, that is, those whose HbA1c changed by >0.5% 60% of the time. These results show that not only do HbA1c levels impact risk, but so do variations in HbA1c. This fluctuation in HbA1c may even be an independent risk factor. That said, the authors do remind the reader that these results were observational, and causation inferences cannot be made. Still, other studies that looked at HbA1c variability show similar increased risk associated with increased variability.   

Practice Pearls: 

• Increased glycemic variability was seen to be associated with increased risk of both macro- and micro-vascular diseases.   
• People with an HbA1c of <7% were most at risk of the negative impacts of significant changes in HbA1c.   
• Change in HbA1c may be an essential point to monitor going forward.   

Li, Sheyu, et al. “Visit-to-Visit HbA1c Variability Is Associated With Cardiovascular Disease and Microvascular Complications in Patients With Newly Diagnosed Type 2 Diabetes.” Diabetes Care, American Diabetes Association, Feb. 2020, care.diabetesjournals.org/content/43/2/426.  

George McConnell, PharmD. Candidate, LECOM School of Pharmacy  

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