When an FDA advisory panel meets Wednesday to review the GLP-1 receptor agonist semaglutide for treating type 2 diabetes, it may have a harder time assessing the risk-benefit balance than with previous agents in this class.
Clinical trial data clearly showed the drug, given weekly by injection, was effective in helping patients improve glycemic control, and showed a clear benefit in reducing major cardiovascular events. But semaglutide also appeared to increase the risk of diabetic retinopathy complications in one of the drug’s seven phase III studies. Briefing information prepared by FDA staff highlighted this risk and signaled that it will be a major discussion topic at the Wednesday meeting.
On the plus side for drugmaker Novo Nordisk, effects on glycemia in the efficacy trials were highly favorable: semaglutide outperformed not only placebo, but also competitors sitagliptin (Januvia), insulin glargine (Lantus), and once-weekly exenatide (Bydureon). And the 2-year cardiovascular outcomes trial called SUSTAIN-6 demonstrated a 26% reduction in risk of major cardiovascular events with semaglutide, including a 35% decrease in rates of stroke and 18% lower rates of myocardial infarction (although, curiously, there was no reduction in cardiovascular death risk).
The unpleasant surprise, though, was a hazard ratio of 1.76 (95% CI 1.11-2.78) in diabetic retinopathy complications in SUSTAIN-6, with about 3.2% of patients experiencing such effects compared with 1.8% of the study’s placebo group over the 2-year study.
FDA staff noted “one hypothesis” that retinopathy may be worsened by rapid, large drops in glycated hemoglobin (HbA1c). “Improving glycemic control should be expected to reduce the risk of retinopathy over the long term,” their briefing document said, and the advisory committee will be asked how much weight the agency should put on the short-term increase seen in SUSTAIN-6. No such effect had been seen in the drug’s phase III efficacy trials, which ran for 30 to 56 weeks.
Novo Nordisk is seeking approval for semaglutide as monotherapy in conjunction with lifestyle modifications for type 2 diabetes. The company is also developing the drug in an oral form, which would be a first for the GLP-1 agonist class; a phase II study reported Tuesday in JAMA found that it was as effective as the weekly injectable form.