FDA Rejects Dapagliflozin for Type 1 Diabetes

Per response letter, the FDA rejects dapagliflozin as a treatment for type 1 diabetes; FDA rejects dapagliflozin  although it was recently approved in Europe and Japan.

The Food and Drug Administration has been very hesitant to approve non-insulin options for type 1 diabetes, and recent FDA rejections include sotagliflozin in March and dapagliflozin in July 2019. The Food and Drug Administration’s recent response letter stated that it would not approve the drug application for dapagliflozin as add on therapy to insulin for type 1 diabetes. 

Dapagliflozin is an oral SGLT2 inhibitor approved for use in type 2 diabetes and is considered safe and effective. Benefits include weight loss, improved blood pressure, and reduction in hyperglycemia. This rejection may be a surprise to many clinicians since SGLT inhibitors are already being used off label in patients with type 1 diabetes.

Dapagliflozin is known to increase the risk of diabetic ketoacidosis, and this concern was voiced at the Food and Drug Administration advisory committee meeting in January 2019. 

The Food and Drug Administration acknowledges the possible benefits of dapagliflozin in type 1 diabetes, but major safety concerns are currently hindering its approval. Unlike the United States, Europe approved dapagliflozin for use in type 1 diabetes, and addressed the safety concerns with structured educational programs. The National Institute for Health Care Excellence in Europe only recommends dapagliflozin use in type 1 diabetes if the patient successfully completed a diabetic ketoacidosis training program. This program includes training on the increased risk of diabetic ketoacidosis with dapagliflozin, how to properly monitor ketones, preventative measures, and treatment guidelines. While this approach seems reasonable and is being implemented in Europe, diabetic ketoacidosis is on the rise in the United States and this concern may have contributed to the Food and Drug Administration’s rejection of dapagliflozin.

Currently, Pramlintide, a synthetic amylin analogue, is the only non-insulin Food and Drug Administration approved option for type 1 diabetes patients, and less than 5% of type 1 patients use this option. There is a desperate need for non-insulin options in this population and the complete response letter from the Food and Drug Administration will guide the pharmaceutical industry to find the best method to address the diabetic ketoacidosis concerns.

Prior to this rejection, Diabetes Care published an international consensus addressing the increased diabetic ketoacidosis risk for type 1 diabetes patients using SGLT inhibitors. This data stated that SGLT inhibitor therapy is a promising treatment in this population and previous studies have already documented the numerous benefits. The consensus acknowledged that SGLT inhibitors are clinically meaningful for type 1 patients, but noted that the increased absolute risk of diabetic ketoacidosis in this drug class cannot be ignored. Proper training for the provider and physician was emphasized to reduce this risk and the following patients are excluded from this therapy; patients on low carbohydrate diets, those who skip meals, or drink alcohol in excess. In addition, patients who lack interest in their care, have recurrent diabetic ketoacidosis, or use insulin pumps are not ideal candidates. 

Based on the international consensus SGLT inhibitors can be used safely in a certain population of type 1 patients when proper training is provided for the provider and patient. Japan and Europe decided to proceed with caution as noted in the international consensus, and approved dapagliflozin for patients with type 1 diabetes, while the United States did not. The United States pharmaceutical industry plans to work with the Food and Drug Administration to address these concerns. If clinicians do plan to continue using SGLT inhibitors off label in patients with type 1, they should heed the Food and Drug Administration’s concern about diabetic ketoacidosis and proceed with caution.

Practice Pearls:

• The Food and Drug Administration’s recent response letter stated that it would not approve the drug application for dapagliflozin as add on therapy to insulin for type 1 diabetes.
• Unlike the United States, Europe approved dapagliflozin for use in type 1 diabetes, and addressed the safety concerns with structured educational programs.
• Although providers should proceed with caution, based on an international consensus SGLT inhibitors can be used safely in a certain population of type 1 patients when proper training is provided for the provider and patient.

References for “FDA Rejects Dapagliflozin for Type 1 Diabetes”:

Danne T, et al. Diabetes Care. 2019;doi:10.2337/dc18-2316.

“Project Information: Dapagliflozin, in Combination with Insulin, for Treating Type 1 Diabetes [ID1478]: Guidance.” NICE, www.nice.org.uk/guidance/indevelopment/gid-ta10374.

Kassey James, Pharm.D. Candidate, LECOM School of Pharmacy