Semaglutide, reduction in glycated haemoglobin and the risk of diabetic retinopathy

Abstract

AimsTo evaluate diabetic retinopathy (DR) data from across the SUSTAIN clinical trial programme.Materials and methodsThe SUSTAIN clinical trial programme evaluated the efficacy and safety of semaglutide, a glucagon‐like peptide‐1 analogue, for the treatment of type 2 diabetes (T2D). In SUSTAIN 6, a 2‐year, pre‐approval cardiovascular outcomes trial, semaglutide was associated with a significant increase in the risk of DR complications (DRC) vs placebo. DR data from across the SUSTAIN trials were evaluated, and post hoc analyses of the SUSTAIN 6 data were conducted. These included subgroup analyses to identify at‐risk patients and a mediation analysis with initial change in glycated haemoglobin (HbA1c; percentage‐points at week 16) as a covariate, to examine the role of the magnitude of reduction in HbA1c as an intermediate factor affecting risk of DRC.ResultsThere was no imbalance in DR adverse events across the SUSTAIN 1 to 5 and Japanese trials. The majority of the effect with semaglutide vs placebo in SUSTAIN 6 may be attributed to the magnitude and rapidity of HbA1c reduction during the first 16 weeks of treatment in patients who had pre‐existing DR and poor glycaemic control at baseline, and who were treated with insulin.ConclusionsEarly worsening of DR is a known phenomenon associated with the rapidity and magnitude of improvement in glycaemic control with insulin; the DRC findings in SUSTAIN 6 are consistent with this. Guidance regarding the early worsening of DR is recommended with insulin. Similar recommendations may be appropriate for semaglutide.

Glucagon‐like peptide‐1 receptor agonists and microvascular outcomes in type 2 diabetes: A systematic review and meta‐analysis

“…Moreover, increased incidence of diabetic retinopathy complications in the SUSTAIN‐6 trial, compared to other semaglutide studies or to cardiovascular outcome trials of other GLP‐1 RAs, could be related to the considerably higher prevalence of baseline diabetic retinopathy complications among trial participants. Notably, in a post‐hoc analysis of the SUSTAIN‐6 trial, no difference in the incidence rate for diabetic retinopathy complications was found between semaglutide and placebo trial arms in patients without pre‐existing diabetic retinopathy . Finally, increased incidence of diabetic retinopathy‐related events in the semaglutide arm could also be associated with the profound and rapid improvement of glycaemic control …”

ADVANCE in context: The benefits, risks and feasibility of providing intensive glycaemic control based on gliclazide modified release

“…A follow‐up mediation analysis of the EMPA‐Reg trial has further suggested that only a modest proportion (23%‐29%) of the overall cardiovascular benefit was attributable to glucose lowering . A further mediation analysis of the SUSTAIN 6 trial has also raised concerns regarding the magnitude and rapidity with which glucose levels are lowered given the unexpected increased risk of retinopathy reported . Indeed, this adverse effect was observed during the first 16 weeks of the trial among patients who had pre‐existing disease and poor glycaemic control .…”

“…A further mediation analysis of the SUSTAIN 6 trial has also raised concerns regarding the magnitude and rapidity with which glucose levels are lowered given the unexpected increased risk of retinopathy reported . Indeed, this adverse effect was observed during the first 16 weeks of the trial among patients who had pre‐existing disease and poor glycaemic control . These findings have fuelled debate and further research as to the probable mechanisms for benefits and risks of SGLT‐2 inhibitors and GLP‐1 agonists, including effects on weight, blood pressure, glomerulotubular feedback, plasma volume and ventricular loading, fuel metabolism, inflammation and endothelial function.…”

Worsening of diabetic retinopathy with rapid improvement in systemic glucose control: A review

“…In the ACCORD BP study, in which 1263 patients with type 2 diabetes were randomized to intensive vs standard antihypertensive therapy, BP control had no effect on the rate of progression of DR (adjusted odds ratio, 1.23; 95% CI, 0.84‐1.79; P = 0.29) . There was also no reported effect of BP on DR complications in the SUSTAIN 6 trial …”