Rapid HbA1c Reduction Not Associated with Early Worsening of Diabetic Retinopathy

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Real-world evidence suggests the rapid reduction of HbA1c is not associated with early worsening in subjects with T2D with mild or moderate nonproliferative DR.

The rapid reduction of hemoglobin A1c (HbA1c) is not associated with early worsening of diabetic retinopathy (DR) in individuals with type 2 diabetes (T2D) with mild or moderate nonproliferative DR, according to new study findings.1

The real-world population-based study conducted in Barcelona, Spain additionally suggested a lack of association between the early worsening of DR and the use of any particular antidiabetic drug in patients with T2D.

“This is important because the vast majority of patients with T2D have no DR or only present early stages of the disease,” wrote the investigative team, led by Dr. Rafael Simo, director of the diabetes and metabolism research unit at Vall d’Hebron Research Institute, Vall d’Hebron University Hospital. “Therefore, in these patients, the optimization of metabolic control should not be delayed.

Poor glycemic control is one of the main modifiable risk factors in reducing the development and progression of DR; however, the rapid improvement of hyperglycemia is another risk factor for DR progression. For those with early worsening of DR, the main variables accounting for this progression include the magnitude of HbA1c reduction and the presence of preexisting DR. Literature has shown the higher reduction of HbA1c, the higher the risk of early worsening of DR.2

However, the influence of the degree of DR on early worsening is not completely understood, as most studies have included subjects without data on DR staging. The aim of the retrospective nested case-control study, led by Simo, was to evaluate whether early worsening is an issue in patients with T2D with mild or moderate NPDR, as well as the relationship between early worsening and antidiabetic drugs. Investigators extracted data from the primary care SIDIAP database (2010 - 2020) and selected 1,150 individuals with early worsening of DR and 1,150 matched controls.

All study participants were 30 years or older, had a diagnosis of T2D in clinical history, ≥2 screening procedures of fundus photography during the observational period, and ≥2 HbA1c determinations before the inclusion date. If DR was suspected, the diagnosis was confirmed by ophthalmologists and classified as normal, mild NPDR, moderate NPDR, severe NPDR, and PDR. Investigators considered “cases” as those individuals whose DR progressed.

For the analysis, the main variable analyzed was the magnitude of the reduction of HbA1c within the previous 12 months. Reduction of HbA1c was categorized as “rapid” if the absolute difference between 2 HbA1c was >1.5% in <12 months and “very rapid” if the change corresponded to a reduction >2% in 6 months.

Upon analysis, investigators did not observe any statistical difference in the absolute reduction of HbA1c between cases and controls (0.13 ± 1.21 vs. 0.21 ± 1.18; P = 0.12). The final HbA1c achieved in the cases and controls was 7.94 ± 1.58 versus 7.87 ± 1.50, respectively.

Moreover, the investigative team found no association between the reduction of HbA1c (rapid or very rapid) and early worsening of DR, in either the unadjusted model or adjusted statistical models that included the main confounding variables: duration of diabetes, baseline HbA1c, and presence of hypertension.

After stratifying by baseline HbA1c, they additionally found that patients with higher levels of HbA1c did not present a higher risk of early worsening of DR. When the analysis stratified the population by antidiabetic drugs, investigators confirmed the lack of relationship between antidiabetic drugs and early worsening of DR.

“Overall, it seems that the intensity and velocity in the reduction of HbA1c rather than the antidiabetic agent used to exert this action is the crucial factor for the early worsening of DR,” investigators wrote. “In this regard, early worsening of DR has been reported after bariatric surgery, thus reinforcing this concept that the risk of early worsening of DR is inherent not to any drug, but to their capacity of lowering HbA1c.”


  1. Simó R, Franch-Nadal J, Vlacho B, et al. Rapid Reduction of HbA1c and Early Worsening of Diabetic Retinopathy: A Real-World Population-Based Study in Subjects With Type 2 Diabetes [published online ahead of print, 2023 Jul 10]. Diabetes Care. 2023;dc222521. doi:10.2337/dc22-2521
  2. Yau JWY, Rogers SL, Kawasaki R, et al.; Meta- Analysis for Eye Disease (META-EYE) Study Group. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care 2012;35:556–564