FDA Advisory Vote Split 8-8 on SGLT Inhibitor for T1D
On Thursday, January 17, Zynquista (sotagliflozin), an SGLT 1 and 2 inhibitor, went before the first-ever regulatory review for a medication of its class for Type 1 diabetes in the United States. Zynquista (sotagliflozin) is developed by Lexicon (partnered with Sanofi). Votes from panel members on the Endocrinologic and Metabolic Drugs Advisory Committee were split 8 to 8 as an advisory on the approval of the drug.
SGLT inhibitors are a class of oral medications approved to treat Type 2 diabetes, some of which are already prescribed off-label to people with Type 1. You may recognize name brands Invokana, Farxiga, and Jardiance – all SGLT2 inhibitors. Studies on their use in Type 1 diabetes (in addition to insulin therapy) show promising results, and now several drugs of this class are seeking approval before the FDA.
The divided vote on Zynquista reflects debate on the risks and benefits of the drug as reported in clinical trials in T1D. An advisory committee vote does not decide FDA approval, but it does inform the process moving forward.
If approved, Zynquista will be the first oral medication to be used alongside insulin developed and tested specifically for people with Type 1 diabetes.
What are the potential benefits of Zynquista (sotagliflozin)?
When taken in addition to daily insulin by people with Type 1 diabetes, sotagliflozin has the potential to reduce A1C, reduce total daily insulin needs, and may help with weight loss, glycemic variability, and overall quality of life.
In three trials involving 2980 patients, sotagliflozin reduced A1C by .3-.4 percentage points, reduced daily insulin demands by 4-9 units per day, and reduced body weight by 2-3 kg after 24 weeks, as reported by Medscape.
What are the potential risks?
The committee’s votes hinged on clinical trial data that showed increase risk of diabetic ketoacidosis (DKA) in patients taking sotagliflozin. 3% of patients on sotagliflozin experienced DKA during the study, while only .4% on placebo did. Notably, nearly half of the DKA episodes in patients taking sotagliflozin occurred in blood glucose levels at or below 13.9 mmol/L250 mg/dL.
One other potential risk of note in an increase in genital mycotic infections.
What can we do about DKA risk?
All patients living with Type 1 diabetes are constantly working to lower their risk of potentially-deadly diabetic ketoacidosis (DKA). While an elevated risk of DKA is dangerous, increased education and awareness might help patients mitigate risks and reap benefits of this new drug.
Sanofi has developed a “risk communication plan” targeting healthcare professionals and patients. It advises healthcare providers not to prescribe sotagliflozin to patients with recent or recurring DKA, who are in ketosis, or who are at risk of ketosis (like those who follow a ketogenic diet). It also suggests careful dose adjustments, routine ketone monitoring, and instructions to stop the drug and seek medical attention for even mildly elevated ketone levels, regardless of symptoms.
Despite the split vote, panel members generally agreed on the nature of the risks and benefits, reports Medscape. Ultimately, approval will hinge on whether the FDA believes a communications plan can successfully mitigate the risks of DKA in patients with type 1 diabetes. Several panel members advised that the proposed risk management strategy be studied to see if it effectively reduces DKA incidence.
A live-tweet from diaTribe during the hearing reads: “Amidst robust discussion about the benefits of
#SGLT compared to the safety risks, Dr. Steve Edelman of TCOYD implored: ‘The burden is with living with diabetes …. So, let the patient have a say in the risk-benefit ratio, myself included.'”
Indeed, Beyond Type 1 worked alongside diaTribe, College Diabetes Network, Children with Diabetes, Diabetes Sisters, and Tidepool to collect testimonials from T1D patients with experience taking SGLT2 inhibitors off-label. These patient testimonials were submitted to the panel ahead this review.
The future of SGLT inhibitors for T1D
An FDA decision on sotagliflozin is expected by the end of March. It has also been submitted and reviewed to the EMA, the European equivalent, for approval. Unlike the FDA process, the EMA review process is not made public, so we know less about the timeline for approval.
AstraZeneca has also submitted Farxiga (dapagliflozin), their SGLT2 inhibitor, to the FDA and the EMA for use in Type 1 diabetes, but there is no news on a decision from either yet. Jardiance (empagliflozin) from Lilly and Boehringer Ingelheim is also expected to be submitted to regulatory bodies for use in Type 1 diabetes. Unlike Zynquista, Farxiga and Jardiance have already been approved by the FDA for Type 2 diabetes.