Glycation Ratios May Benefit Risk Detection for Microvascular Complications

Laura Bovee, MD, MS

Credit: ADA

Positive discordance as measured by a glycation ratio of glucose management indicator and hemoglobin A1c (GMI/A1c) was associated with a more than two-fold increased risk for diabetic retinopathy and nephropathy, according to new research.¹

The data, presented at the 83rd Scientific Sessions of the American Diabetes Association (ADA 2023), suggest the use of the GMI/A1c ratio may allow for increased identification of patients at high risk for microvascular complications.

“This supports our hypothesis that with the decreasing glycation ratio, we see increased association of retinopathy,” presenting investigator Laura Bovee, MD, MS, from the University of Washington said at ADA 2023.

Discordance between glycated hemoglobin A1c and mean glucose is common, even in the absence of known risk factors, such as chronic kidney disease (CKD) and anemia. Proposed mechanisms for this discordance include increased glycation and increased red blood cell survival. Prior analyses from the investigative team have suggested clinically significant discordance between A1c and GMI in half of the study participants.²

Multiple indices have been used to quantify and analyze discordance, including the glycation ratio (GMI/A1c). As the glycation ratio decreases, positive discordance will increase. Investigators suggested that increased hemoglobin glycation is linked to the formation of advanced glycation end products (AGEs) on hemoglobin.

As a result, if the formation of AGEs on hemoglobin is analogous to the process in the retina and the kidney, then positive discordance and increased glycation may be associated with an increased risk for microvascular complications. The investigative team hypothesized the glycation ratio could identify those with positive discordance who have an increased risk of microvascular complications.¹

Two groups were defined for the analysis: GR <0.9 (positive discordance) and GR >0.9. Investigators then analyzed these groups for complications of retinopathy and nephropathy and then modeled the relationships graphically. The retrospective review consisted of 717 participants with diabetes at the University of Washington Diabetes Care Center from 2012 - 2019, a total of 661 participants were included in the analysis after exclusions.

Diagnosis of microvascular complications was defined in the electronic medical record (EMR) problem list; retinopathy consisted of all types of proliferative and non-proliferative and nephropathy was confirmed by chart review with lab evidence of albuminuria and/or decreased eGFR.

The population included 600 patients (90.8%) with type 1 diabetes and 54 patients (8.2%) with type 2 diabetes, with a mean CGM wear duration of 24.7 days. All patients had A1C and sensor data obtained fewer than 4 weeks apart. Of this population, 107 participants (16.2%) were shown to have a glycation ratio <0.9 with positive discordance and 554 participants (83.8%) had a glycation ratio >0.9. Those with a glycation ratio <0.9 had statistically higher mean HbA1c of 8.4% compared with those with a glycation ratio >0.9 (7.1%), as well as a higher mean GMI (6.8%).

Upon analysis, investigators found that retinopathy was more common in 42.3% of the group with a glycation ratio <0.9, compared with 25.5% of those with a glycation ratio >0.9 (odds ratio [OR], 2.05; 95% CI, 1.33 - 3.14). Moreover, the analysis showed 24.3% of those with positive discordance showed nephropathy compared with 10.2% of those with a glycation ratio >0.9 (OR, 2.83; 95% CI, 1.68 - 4.77). The team modeled the data as a continuous nonlinear function and revealed an inverse relationship between GMI/A1c and diabetic retinopathy.

Investigators noted the limitations of the study included its retrospective, one-center analysis design, less reliable CGMs, room for improved diagnostic specificity, the multifactorial nature of elevated A1c, and possible confounding from A1c and CKD. Bovee indicated additional analysis of confounding factors is needed and further research is required to determine the external validity of the analysis findings.

“In conclusion, the glycation ratio can be readily calculated from available data,” Bovee said in her presentation. “It may identify those at higher risk for microvascular complications.”

References

1. Bovee L, Perlman J, Gooley T, Hirsch IB. Association of Diabetic Retinopathy with A1C and Glucose Management Indicator Discordance. Oral presentation at the 83rd Scientific Sessions of the American Diabetes Association. June 23 – 26, 2023.
2. Perlman JE, Gooley TA, McNulty B, Meyers J, Hirsch IB. HbA1c and Glucose Management Indicator Discordance: A Real-World Analysis. Diabetes Technol Ther. 2021;23(4):253-258. doi:10.1089/dia.2020.0501