Development of diabetic retinopathy (DR) depends on many factors, including duration of diabetes mellitus (DM), hypertension, race, and glycemic control as measured by hemoglobin A1c (A1c). Hemoglobin A1c, which is the 3-month average of red blood cell glycosylation levels, is among the most widely recognized factors that impact DR progression.1 This review summarizes the effect of A1c on the progression of DR, the cellular mechanisms and effects of hypoglycemia and rapid glycemic control on DR, and the role of glucagon-like peptide-1 (GLP-1) receptor agonists in DR. The implications of these findings on treatment and management are also discussed.
A1c as a Predictor for Diabetic Retinopathy
Severity
Diabetic retinopathy is typically graded on a 4-point severity scale ranging from 0 to 4: none (0); mild, characterized by microaneurysms (1); moderate, involving microaneurysms and hemorrhages in 1 to 3 quadrants (2); severe, with high-grade hemorrhage in all 4 quadrants, venous bleeding in at least 2, or moderate intraretinal microvascular abnormality (3); and proliferative, marked by neovascularization, vitreous hemorrhages, or preretinal hemorrhages (4).2,3 Because the severity of DR is associated with worse visual outcomes and thus quality of life,4 this grading system has significant clinical implications in patient care.
Progression
Understanding the progression of DR is important for effective management. Proliferative DR is the most severe form and is a common cause of blindness worldwide.5 Within 4 years of initial diagnosis, approximately 16% of mild cases and 23% of moderate cases progress to proliferative DR; of severe cases, approximately half progress to proliferative DR within 1 year.6
Increased A1c is a known risk factor associated with the progression of DR.7 One retrospective study, for example, followed patients from presentation of DR to a 3-year follow-up. A1c was found to be the strongest predictor of not only development of retinopathy, but also worsening of pre-existing retinopathy, progression to proliferative stages, and incidence of macular edema.8 Thus, regardless of the stage of DR, maintaining glycemic control is a crucial preventative measure for anyone at risk.
Risk Factors
Given the prevalence of DR and its severe consequences, it is important to identify risk factors that contribute to its development. These risk factors include obesity, hypertension, and poor glycemic control — defined as A1c levels greater than 8.0%.9 Pooled analyses of nearly 23,000 patients demonstrated a positive association between increased A1c levels and DR prevalence: among patients with an A1c ≤7.0% vs >9.0%, the prevalence of DR was 18.0% vs 51.2%, respectively.10 A1c is a crucial, controllable risk factor for the development of DR.
Although there is a clear association between A1c and DR, fasting blood glucose (FBG) also appears to be a predictor.11 In the literature, however, debates persist regarding whether FBG or A1c holds greater predictive value.12,13 This inconsistency prompts further investigation into the relationships between glycemic markers and DR.
Cellular Mechanisms of Hypoglycemia on Diabetic Retinopathy Exacerbation
Despite established research that hyperglycemia may exacerbate DR, recent studies have revealed how hypoglycemia can paradoxically worsen DR during DM management.14 This side effect of tight glycemic control involves the hypoxia-inducible factor (HIF)-1 pathway and its unique response to low glucose levels in the retina. The HIF-1α protein controls the expression of genes involved in angiogenesis and the production of vasoactive substances, including vascular endothelial growth factor (VEGF) and angiopoietin-like 4 (ANGPTL4).15,16
Under healthy conditions, HIF-1α responds to cellular stress based on oxygen levels.17 In sufficiently oxygenated states, HIF-1α is degraded quickly. Under hypoxic conditions, however, HIF-1α stabilizes and translocates to the cell nucleus to activate genes that help the cell adapt to hypoxia. In hypoglycemic states, the HIF-1α translation becomes upregulated independent of oxygen levels.14 By promoting new blood vessel formation and adjusting blood flow, this mechanism helps to maintain a steady glucose supply for retinal cells. Thus, in the setting of hypoglycemia in DR, HIF-1α dysregulation may further damage the microvasculature of the retina: excessive angiogenesis and altered vascular permeability may induce DR and its classic findings, including pericyte loss, endothelial cell injury, microaneurysms, and capillary dropout.18 Diabetic macular edema and proliferative DR may ensue.19
By promoting the formation of fragile and abnormal new blood vessels and increasing vascular permeability, the actions of HIF-1α in response to hypoglycemia may worsen retinal ischemia.14 This hypoxia creates a vicious cycle by further increasing HIF-1α activity and leading to more damage. Thus, the HIF-1 pathway is a potential therapeutic target in mitigating the progression of DR. Because both hyperglycemia and hypoglycemia can trigger processes that damage retinal microvasculature, it is important to continuously monitor glycemic variability in managing DR.
Early Worsening of Diabetic Retinopathy After Glycemic Control
Retinal damage may also be seen in circumstances of relative hypoglycemia, such as the abrupt and significant reduction in glucose concentration to a normal range in patients with uncontrolled DM who begin glucose control.20 Studies have observed a paradoxical early worsening of DR (EWDR), a phenomenon that occurs in 10% to 20% of patients with DR after abrupt glycemic control. Early worsening of DR may be temporary and regress, especially in patients with mild DR; in others, it may cause severe damage requiring laser correction. The most important risk factors for EWDR are the cumulative exposure — both extent and duration — to hyperglycemia and the severity of DR at baseline.21
Insulin therapy was the first form of glucose control to be studied with respect to EWDR in the 1990s. In a multivariable analysis of a group of 1,378 diabetic patients, those who changed from diet therapy or oral hyperglycemic agents were significantly more likely to experience worsened DR than those who did not change. These patients were also up to 3 times more likely to experience blindness or severe visual impairment due to DR. These analyses remained significant even after controlling for A1c.22 However, longitudinal studies have shown that despite potential EWDR, insulin treatment still limits DR progression long term.23,24 The benefits of long-term insulin for DM patients far exceed the risks.
Although EWDR was first observed more than 30 years ago, its underlying mechanisms remain unclear. One hypothesis cites disruptions in the axis between growth hormone and insulin-like growth factor (IGF)-1, in which increased levels of IGF-1 — established to be higher in those with DR — may mediate EWDR. Others suggest that VEGF expression, a key component of DR pathogenesis, may increase due to lowered glucose concentrations and increased insulin-dependent signaling. More research is necessary to elucidate our understanding of EWDR.21
Role of GLP-1 Agonist Drugs in DR
Glucagon-like peptide-1 (GLP-1) receptor agonists are a relatively new class of diabetes medications that stimulate increased insulin secretion, decreased glucagon secretion, and slowed gastric emptying.25 Because these drugs resist physiologic degradation, they have longer-lasting effects than natural GLP-1, and thus aid in reducing A1c and increasing satiety. As these medications are being increasingly prescribed for patients with DM,26 it is important to understand their potential effects on DR.
GLP-1 receptor agonists may contribute to EWDR: one meta-analysis found the magnitude of A1c reduction in patients on GLP-1 receptor agonist treatment to be directly correlated with an increased risk of retinopathy.27 However, a meta-analysis of 20 randomized controlled trials found that GLP-1 receptor agonist treatment in and of itself did not increase risk of DR among type 2 DM patients.28 Thus, selecting GLP-1 agonists that have minimal effects on hypoglycemia may be most appropriate for controlling DR.
Another meta-analysis of 93 trials investigating the influence of GLP-1 drugs on the development of DR found that, compared to placebo, GLP-1 users had an increased risk of early-stage DR; compared to insulin-users, they had lower risk of late-stage DR.25 Both these relationships were mediated primarily by albiglutide, although the mechanism by which albiglutide, rather than the other drugs, achieved these effects remains unknown. Further research should be conducted to better understand the role of each specific medication on DR trends to better inform prescribing practices.
Notably, 1 mechanism by which GLP-1 receptor agonists may aid DR treatment is through prevention of retinal degeneration. Not only have GLP-1 receptors been found to be abundantly expressed on human retinas, but their stimulation — both topical and systemic — results in an increase of pro-survival signaling pathways. Especially as the systemic effects were observed in the absence of decreased blood glucose, these results indicate that GLP-1 receptor activation in and of itself may protect against retinal degeneration.29
In addition, GLP-1 receptor activation reduces extracellular glutamate toxicity and thus glutamate-induced apoptosis and inflammation, both major mediators of DR.26 Together, these pathways suggest that GLP-1 receptors may be a promising therapeutic target, even independent of their role in glucose control in DM.
Conclusions and Implications
Glycemic control is decidedly a crucial factor to consider in managing DR. However, given the complexity of DR management and ongoing debates on the exact mechanisms of glycemic control on disease progression, physicians should adopt a comprehensive approach to DR management. This strategy includes regularly monitoring A1c and FBG to maintain levels within a patient-specific target range, while being wary of the potential for EWDR with rapid glycemic control.
Given that many other systemic, environmental, and genetic factors — including blood lipid levels, hypertension, and race1 — may contribute to a patient’s DR risk profile, physicians should consider broader factors in management as well. Regular evaluation, patient education on glycemic control and lifestyle modifications, and timely intervention for DR are critical. This holistic approach may help improve patient outcomes. RP
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