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FDA advisory committee supports once-weekly semaglutide for type 2 diabetes
An FDA advisory panel on Wednesday voted 16 to 0, with one abstention, in favor of recommending approval for the GLP-1 receptor agonist semaglutide for the indication of improving glycemic control in adults with type 2 diabetes.
In recommending the drug’s approval as an adjunct to diet and exercise, members of the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) also expressed concern regarding a potential increase in the risk for complications related to diabetic retinopathy observed in the SUSTAIN-6 trial, where retinopathy was a prespecified secondary outcome. However, most panel members agreed the issue could be addressed with wording on the drug’s label, which Novo Nordisk offered to do during its morning presentation.
In explaining his “yes” vote, Paul M. Palevsky, MD, chief of the renal section of VA Pittsburgh Healthcare System and professor of medicine and clinical and translational science at the University of Pittsburgh School of Medicine, called the observed improvement in HbA1c with semaglutide “impressive.”
“There was no cardiovascular signal for harm,” Palevsky said after the panel voted. “The other adverse events, other than retinopathy, were as would be expected for this class and were not a concern. Retinopathy is, in my view, a modest concern that is outweighed by the benefit otherwise seen. I support the sponsor’s proposal for labeling similar to that for insulin, in terms of the risk for retinopathy progression.”
“It would be very nice if we had a real retinopathy study, with documented retinal exams, to resolve this question [of risk], and that would need to be a longer-term study than a 2-year study,” Palevsky added.
The panel’s recommendation follows overall positive results from the SUSTAIN clinical trial program, which included more than 8,000 adults with type 2 diabetes.
In the SUSTAIN program, semaglutide demonstrated statistically significant and sustained blood glucose control when compared in trials with sitagliptin, exenatide extended-release, once-daily insulin glargine U100 and placebo. Weight loss, a secondary endpoint, was also demonstrated in all semaglutide arms.
The cardiovascular outcomes trial, SUSTAIN 6, demonstrated a reduction in CV risk compared to placebo, as an add-on to standard of care in patients with established CVD.
The panel’s one abstaining member, Yves D, Rosenberg, MD, MPH, chief of the atherothrombosis and coronary artery disease branch at the National Heart, Lung and Blood Institute at the NIH, said he did not want to cast an “uncomfortable yes” vote.
“I really wanted to vote ‘yes,’ and I think there is ample reason that this drug should be improved,” Rosenberg said following his vote. “I wanted to make a point to the FDA that there should be follow-up studies. It’s a tremendous lost opportunity, first, by not designing the trial with a longer follow-up, and not large enough to answer the question of cardiovascular benefit, and second, for not doing the longer follow-up to address the concerns regarding retinopathy.”
Early risk, late benefit
Advisory committee members considered several draft points relating to semaglutide’s efficacy and safety endpoints, including the risk for retinopathy complications. Presenters from both the FDA and Novo Nordisk suggested that the observed retinopathy complications were likely due the drug’s rapid glucose-lowering effect in patients and were not a drug-specific effect.
In an NIH presentation, Emily Y. Chew, MD, deputy director of the National Eye Institute, said results from past studies like the DCCT and ACCORD suggest that any observed worsening of retinopathy that accompanies a lowering of blood glucose is “rather transient” and typically followed by an observed, long-term benefit.
“This early worsening is very familiar to us in diabetic [eye] research,” Chew said. “Intensive glycemic control has a huge effect on diabetic retinopathy.”
Addressing the concerns relating to diabetic retinopathy, Lloyd Paul Aiello, MD, PHD, professor and vice chair of the department of ophthalmology at Harvard Medical School, director of the Beetham Eye Institute and vice president of the Joslin Diabetes Center, noted that an “early worsening phenomenon” with respect to retinopathy has been observed with other agents that rapidly improve blood glucose control, including insulin, after bariatric surgery and after pancreatic transplantation, he said.
“The risks are offset by the reductions in long-term retinal complications,” Aiello, speaking on behalf of Novo Nordisk, said during the meeting.
In an FDA ophthalmology consult outlined in the briefing documents, reviewers noted that, based on the data, there is “no reason to restrict semaglutide with respect to population or dosing schedule,” adding that there is no reason to require additional ophthalmic follow-up.
Discussing the drug’s safety profile, Stephen Gough, MD, FRCP, senior principal clinical scientist with Novo Nordisk, noted that, in general, most adverse events in the SUSTAIN program were gastrointestinal and were mild and transient in nature, consistent with the GLP-1 receptor agonist class. Serious adverse event rates were low in the SUSTAIN program, he added.
Following Novo Nordisk’s presentation, several panel members inquired about label wording on insulin products, which note an increased risk for worsening diabetic retinopathy with a rapid reduction in blood glucose.
Gough, who called semaglutide’s HbA1c benefit “greater than ever we expected,” said the company plans to include language about diabetic retinopathy that parallels labeling for insulin products, including the management of patients showing signs of early worsening diabetic retinopathy.
The advisory panel’s recommendations are nonbinding, although the FDA often follows its suggestions. – by Regina Schaffer
For more information:
Novo Nordisk Briefing Information