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HbA1c Changes as a Predictor of Cardiovascular Disease Incidence

Jun 15, 2021
Editor: Steve Freed, R.PH., CDE

Author: Laura Martínez López, PharmD. Candidate 2021, Lake Erie College of Osteopathic Medicine, College of Pharmacy

HbA1c variability and swings between hypo- and hyperglycemia can increase risk of developing cardiovascular disease.

Lately, more investigations have taken place looking for associations between elevated blood sugar and cardiovascular diseases. Complications in diabetes management can lead to eye damage, kidney failure, neuropathy, high blood pressure, and high cholesterol. Understanding the condition can sometimes be overwhelming, and some patients may experience some burden when they are diagnosed.  Large glycemic variability is associated with poor lifestyle modifications, poor adherence to medications, and poor self-management.  


Previous studies have shown that variability in HbA1c is associated with adverse outcomes and mortality. A systematic review and meta-analysis from 2015 showed that variations in HbA1c could lead to microvascular and macrovascular complications and mortality. They also observed that the variability in HbA1c and the correlation with cardiovascular disease were also present in non-diabetic patients.  

Researchers conducted a recent retrospective cohort study to investigate the association between visit-to-visit HbA1c changes and the risk of developing cardiovascular complications or diseases for patients with type 2 diabetes. This study includes data from January 2013 to April 2018, and includes patients with type 2 that had at least four HbA1c levels obtained within two years of their first diagnosis on record. The study included 29,260 participants with type 2 diabetes with a mean age of 66. The follow-up was electronic. They measured HbA1c, HbA1c Standard Deviation (HbA1c SD), HbA1c coefficient of variation (HbA1c CV), and adjusted HbA1c SD to minimize effects on different numbers in HbA1c values.  

As a primary outcome, they measured the incidence of cardiovascular events. The study utilized ICD-9 and ICD-10 to identify coronary artery disease, stroke, and cardiovascular disease events. The researchers used the Cox Proportional Hazards regression for the incident of cardiovascular events. The Cox Proportional Hazard Ratio and regression were used to estimate the association of the HbA1c changes and the risk of first and recurrent hospitalization for severe hypoglycemia. Patients in this study were followed for four years.  

The results showed that patients with greater HbA1c changes through visit-to-visit evaluations were younger, had higher BMI, high blood pressure, and altered lipid profile. Also, during the four years’ follow-up period, 3,746 patients developed cardiovascular disease. The hazard ratio reported for the cardiovascular diseases during the four HbA1c SD values were 1.00, 1.30 (95% CI: 1.18-1.42), 1.40 (95% CI: 1.26-1.55), and 1.59 (95% CI: 1.41-1.77) respectively with p<0.001. They observed a similar association for HbA1c CV and adjusted HbA1c SD.  

On the other hand, when researchers performed the mean follow-up at 3.66 years, diagnosis of coronary heart disease occurred in 2,348 patients. The hazard ratio reported for coronary heart disease incidence in the four HbA1c SD readings was 1.00, 1.31, 1.40, and 1.71 (p<0.001). Researchers found a similar trend for HbA1c CV and adjusted HbA1c SD. Moreover, during a follow-up period of 4.31 years, they reported 1,851 new stroke cases. The hazards ratios for stroke were 1.30 (95% CI: 1.17-1.43) for HbA1c SD, 1.40 (95% CI: 1.16-1.55) for HbA1c CV, and 1.20 (%95 CI: 1.11-1.30) for adjusted HbA1c SD.  

They found a positive association between the HbA1c variability and the risk of cardiovascular disease. This association was not present in patients treated with alfa-glucosidase inhibitors, GLP-1 receptor agonists, meglitinides, thiazolidinediones, and SGLT-2 inhibitors.  

After a follow-up period of 4.43 years, 1,211 patients were hospitalized due to a hypoglycemia event. The hazard ratio reported for the four HgA1C SD readings were 1.00, 1.60 (95%CI:1.27-2.01), 2.54 (95% CI: 2.04-3.18), and 3.00 (95% CI: 2.36-3.82) for a p<0.001. A similar association was also found for HbA1c CV and adjusted HbA1c SD.  

In this study, there was a direct correlation between HbA1c variability between visits and the risk of developing cardiovascular diseases. Some limitations found in this study include the lack of education level assessment as well as family income. Also, the cardiovascular risk factor was based on a physician’s diagnosis. Other factors not assessed in this study include the family history of diabetes, related chronic diseases, dietary factors, and physical activity. Finally, the results showed in this article cannot be generalized because the patients were from Louisiana, and the characteristics of patients may be different depending on the area. After evaluating the results, there is an association between visit-to-visit HbA1c variability and cardiovascular diseases in patients with type 2 diabetes.  

Practice Pearls:  

  • Both higher blood sugar and lower blood sugar can increase the risk of cardiovascular disease.  
  • No significant association between HbA1c variability and risk of cardiovascular events was present in patients taking alfa-glucosidase inhibitors, GLP-1 agonists, SGLT-2 inhibitors, meglitinides, and thiazolidinediones.  
  • A sedentary life can indirectly increase your HbA1c and can lead to cardiovascular diseases in the future. 


Shen, Y. et al. Association Between Visit-To-Visit HbA1c Variability and The Risk Of Cardiovascular Disease In Patients With Type 2 Diabetes. Diabetes Obes Metab. 2021 

Leon, B. et al. Diabetes and Cardiovascular disease: Epidemiology, Biological Mechanisms, Treatment Recommendations, and Future Research. World J Diabetes (2015).  


Laura Martínez López, PharmD. Candidate 2021, Lake Erie College of Osteopathic Medicine, College of Pharmacy