US FDA Panel Split on Sotagliflozin for Type 1 Diabetes

Miriam E. Tucker

January 18, 2019

A US Food and Drug Administration panel has delivered a tie vote on whether the benefits outweigh the risks of sotagliflozin (Sanofi/Lexicon) as an adjunct to insulin in the treatment of type 1 diabetes.

The FDA's Endocrinologic and Metabolic Drugs Advisory Committee's vote was 8 to 8 on the use of sotagliflozin, a dual inhibitor of sodium-dependent glucose cotransporter 1 (SGLT1) and SGLT2, in people with type 1 diabetes for whom optimal glycemic control is not achieved with insulin alone.

If approved, it would be the first oral medication for type 1 diabetes. The companies plan to use the brand name Zynquista.

Despite the split vote on the benefit/risk analysis, panel members generally agreed about both the benefits and risks of the drug in patients with type 1 diabetes. On the one hand, in three pivotal trials involving 2980 patients who were randomly assigned to receive 200 mg or 400 mg of sotagliflozin or placebo, the drug significantly reduced hemoglobin A1c by about 0.3 to 0.4 percentage points, total insulin dose by about 4 to 9 units a day, and body weight by about 2 to 3 kg at 24 weeks. It also reduced glycemic variability and improved patient satisfaction.

But, the risk for diabetic ketoacidosis (DKA) with sotagliflozin was significantly higher compared to placebo: 3% (56 of 1748 patients) vs 0.4% (5 of 1229 patients) in the three trials, despite strict study protocols that involved patient and investigator education about recognition of DKA signs and symptoms, monitoring of ketones with home monitoring equipment that was provided, and intervention instructions.

"The magnitude of the risk of DKA in the real-world setting may be greater than in a clinical trial setting," FDA reviewer Mitra Rauschecker, MD, said during the agency's presentation of its analysis of the sponsor's data.

DKA occurred at blood glucose levels at or below 250 mg/dL in nearly half of the patients. Moreover, the DKA risk continued for the entire 52 weeks of evaluation and was seen across patient subgroups.

Sotagliflozin was also associated with increased genital mycotic infections and had no effect on the rates of severe hypoglycemia.

Votes Hinged on Whether DKA Risk Can Be Mitigated in the Real World

Klaus Henning Jensen, MD, head of diabetes cardiovascular and metabolism development at Sanofi, presented the company's proposed "risk communication plan," which targets both healthcare providers and patients.

The plan begins with patient selection. It advises against starting the drug in patients with recent or recurrent DKA, ketosis at baseline, or who have excessive ketosis risks, such as those who follow ketogenic diets.

The proposal also involves careful insulin dose adjustments to avoid both hypoglycemia and ketosis, routine ketone monitoring, and instructions to stop the drug and seek medical attention for mildly elevated ketone levels with clinical symptoms or moderately elevated ketone levels regardless of symptoms.

Communication would be accomplished via product labeling, letters to healthcare providers, patient alert cards, and an online medication guide.

In general, the panel's votes hinged on whether they felt those measures were sufficient to mitigate the risk and to allow the drug onto the market for use in patients with type 1 diabetes.

Daniel Budnitz, MD, director of the Medication Safety Program at the US Centers for Disease Control and Prevention, Atlanta, Georgia, voted yes despite concern about the DKA risk: "I think this drug does meet the bar for approval based on A1c-lowering.... For some patients, the benefit-risk ratio may be positive."

But, Budnitz added, "I'm voting yes with the reservation that we have to have a [risk management strategy] that essentially mimics the clinical trial conditions," including providing patients with ketone monitoring equipment and requiring documentation of insulin optimization prior to drug initiation, as had been done in the trials.

Jack A. Yanovski, MD, chief of the Section on Growth and Obesity at the National Institutes of Health, Bethesda, Maryland, voted no, but observed "this was a very difficult decision.

"I vacillated back and forth.... It's very clear there is a desperate need for additional approaches to type 1 diabetes, and there are definite advantages to this drug. However, I don't think it's quite ready for prime time. I think additional studies should be done before this is released on a wider public."

Yanovski advised, as did several other panel members, that the proposed risk management strategy be tested to ensure that it does reduce DKA incidence before the FDA allows marketing of sotagliflozin.

The panel also expressed varying opinions about whether the drug should be approved at both 200-mg and 400-mg doses. Some advised that only the 200-mg dose be approved so as to reduce the DKA risk, whereas others noted that some patients may need 400 mg for efficacy.

A decision on approval of sotagliflozin by the FDA is expected by the end of March, although it's not clear, as the federal government shutdown drags on, whether the agency will have to delay approvals of products.

Consensus Document on Risk Management of DKA Imminent

A document entitled International Consensus on Risk Management of Diabetic Ketoacidosis in Patients With Type 1 Diabetes Treated With Sodium-Glucose Cotransport (SGLT) Inhibitors was available at the FDA advisory committee hearing and is due to be published in Diabetes Care in the coming days.

It will cover off-label use in patients with type 1 diabetes of the SGLT2 inhibitors currently approved for treating type 2 diabetes, as well as sotagliflozin, should it be approved.

Recommendations will be similar to those proposed by Sanofi and that are endorsed by panel members regarding appropriate patient selection, insulin dose adjustments, low-dose initiation, ketone monitoring, SGLT inhibitor discontinuation instructions, and DKA treatment.

The FDA screens advisory panel members for conflicts of interest and grants waivers for participation if necessary. No waivers were granted for this panel.

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