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FDA advisory committee splits vote recommending dual SGLT inhibitor for 1 diabetes
The Endocrinologic and Metabolic Drugs Advisory Committee voted 8-8 in a decision on whether to recommend approval of a new drug application for oral sotagliflozin, a first-in-class dual SGLT1 and SGLT2 inhibitor for type 1 diabetes, with several members expressing concerns about an observed risk in diabetic ketoacidosis and calling for a risk evaluation and mitigation strategy if the therapy is approved.
Insulin and pramlintide are the only drugs currently approved for the treatment of type 1 diabetes in the United States. The advisory panel’s recommendations are nonbinding, although the FDA often follows its suggestions.
In discussion following the split decision, committee members who voted both in favor of and against approving the drug cited similar concerns about incidence of diabetic ketoacidosis (DKA) observed across three phase 3 trials, which the FDA noted was the most notable and concerning adverse reaction associated with sotagliflozin (Zynquista, Sanofi). In agency analyses, sotagliflozin was associated with an approximately eightfold increase in DKA risk vs. placebo (95% CI, 3.1-19.9). The estimated number needed to harm was approximately 26 patient-years of exposure to sotagliflozin to observe 1 additional DKA event, according to the FDA (95% CI, 20.1-38.5).
Benefit vs. risk
“I did not see clear evidence that the benefit outweighs the risk [of DKA] here,” Michael Blaha, MD, MPH, assistant professor of cardiology and epidemiology and director of clinical research at the Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, said following his “no” vote. “And this is in a clinical trial setting with exquisite follow-up of these patients. I appreciate the anecdotes that we heard during public comment [suggesting benefit] … but we didn’t get to hear from people who had DKA, and their life might have changed from that potentially life-threatening outcome. An eightfold increase in risk — I couldn’t get over that.”
Additionally, subgroup analyses showed a consistently elevated DKA risk associated with sotagliflozin, with estimated hazard ratios ranging from 4 to 11, and number needed to harm ranging from 11 to 37, according to the FDA.
Before voting, the committee discussed four questions focusing on the safety and efficacy of sotagliflozin, including the drug’s effect on glycemic response, body weight and risk for hypoglycemia, as well an observed DKA risk in clinical trials.
Sotagliflozin works by inhibiting the SGLT1 and SGLT2 proteins responsible for glucose regulation. Inhibition of SGLT1 blunts and delays the rise in glucose after meals by reducing glucose absorption in the proximal intestine, whereas SGLT2 inhibition prevents the kidneys from reabsorbing glucose back into the blood. The proposed dosing regimen is 200 mg once daily, before the first meal of the day. The dose may be increased to 400 mg once daily in patients tolerating the 200 mg once daily dose. The two doses were analyzed in comparison with placebo in three phase 3 studies.
In briefing documents released Tuesday, the FDA noted that no formal testing was performed comparing the two doses; however, there was a slight trend toward greater efficacy for glycemic response with the 400 mg dose vs. the 200 mg dose, as well as greater reductions in body weight with the 400 mg dose.
“It may be useful to consider these results in the context of the overlapping exposure between the two doses,” FDA officials wrote.
Need for options
Several committee members, while noting the risk for DKA, also emphasized that people with type 1 diabetes have few options aside from titrating insulin dosing. Consumer representative Anna McCollister-Slipp, founder of VitalCrowd in Washington, D.C., said she lives with risk daily as a person with type 1 diabetes.
“We need options,” McCollister-Slipp said after her “yes” vote. “We live in a world of risk, with or without this medication. This medication helps mitigate that risk and makes it more possible to be able to function and live a healthy life. We need to trust patients and physicians to be able to work through the risk-benefit profile.”
Rebecca Brown, MD, Lasker Clinical Investigator with the National Institute of Diabetes and Digestive and Kidney Diseases at the NIH, said the benefit of sotagliflozin was not fully captured by the documented change in HbA1c.
“I am convinced by the reductions in minute-to-minute variability,” said Brown, who voted “yes.” “That said, I have serious hesitations about the safety of this drug in the broad community with type 1 diabetes. I think there will be a subset for whom the benefits will outweigh the risk, but that certainly will not be true for every patient. The task going forward will be to have a [risk evaluation and mitigation] strategy … to identify patients who can use this drug in the safest way possible.”
In Sanofi’s briefing documents supporting approval of sotagliflozin, industry officials noted that, across the phase 3 studies, sotagliflozin improved HbA1c without the excessive weight gain caused by intensification of insulin treatment and with reductions in systolic blood pressure.
“Over time, both of these effects would be expected to lower CV risk,” industry officials wrote.
The officials also noted that the increase in risk for DKA with sotagliflozin can be managed with appropriate measures, such as adjustment in insulin dose, similar to management with an SGLT2 inhibitor.
“If approved and used in accordance with the product label, the benefits of sotagliflozin as an adjunct to insulin for the treatment of [type 1 diabetes] will outweigh the risks,” industry officials wrote. “Sotagliflozin improves multiple aspects of glycemic control without increasing the risk of hypoglycemia or excessive weight gain. These effects will improve the function and well-being of patients with [type 1 diabetes] whose disease is not currently well-controlled on standard-of-care insulin therapy and glucose management.”
The committee offered mixed feedback regarding approval of the two doses of sotagliflozin, with several members expressing that the 400 mg dose, in particular, would further increase the risk for DKA, without much additional benefit for the patient. – by Regina Schaffer
Reference:
FDA briefing information. Available at: https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM629485.pdf. Accessed on: Jan. 16, 2019.
Sanofi-Aventis briefing information. Available at: https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM629487.pdf. Accessed on: Jan. 16, 2019.
Editor's note: This article was updated on January 17 to include details of the committee vote.
Perspective
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I’m not surprised this ended up being a split decision. The committee members are being asked an extraordinarily difficult question with respect to this drug. People die from DKA. We did not have deaths from DKA in these particular studies, but these people were also watched very carefully. Patients may not do as well if and when the drug becomes available more generally.
Many feel strongly that there need to be more options for people with type 1 diabetes and that people do not have enough compassion and empathy for what it’s like to live with this disease day to day. That’s a valid argument. With any therapy, there are always risks and benefits. Clearly, the higher incidence of DKA with this drug is the big question, but for many people with type 1 diabetes, it’s extremely difficult to get control, and studies show that there is better control when adding this agent. The risk-benefit is worth it to many of the people, and it was clearly OK during the studies or else the studies would have been stopped. So what happens when people with type 1 diabetes are prescribed this drug and are not followed as carefully?
It’s a really hard question for FDA to answer.