FDA declines to approve first oral medication for type 1 diabetes

Originally published HERE

The U.S. Food and Drug Administration (FDA) issued a Complete Response Letter (CRL) today regarding Zynquista (sotagliflozin) for use by patients with Type 1 diabetes. Zynquista is a dual SGLT-1/2 inhibitor, and would have been the first oral medication approved for people with T1D to be used in conjunction with insulin therapy. Lexicon and Sanofi announced the news in a joint press release. In the statement, the partners said they’d “work closely with the FDA to determine the appropriate next steps.”

A CRL is issued when the FDA declines to approve a drug in its current form and has outstanding questions. It is not an outright rejection, but the responsibility now shifts back to the product sponsor(s) — in this case Lexicon and Sanofi who developed the drug — to address deficiencies raised.

SGLT inhibitors are not new to the diabetes landscape — SGLT-2 inhibitors have been used since 2013 in the United States to treat Type 2 diabetes. In fact, people with Type 1 diabetes have been regulating their blood sugars with off-label use of the drugs for just as long.

Recognizable name brand SGLT-2 inhibitors include Farxiga, Invokana and Jardiance. Studies on their use in T1D patients show promising results, and Farxiga and Zynquista are currently being reviewed by the European Medicines Agency (EMA) for usage by people with T1D.

Trial results for Zynquista identified a notable reduction in HbA1c levels and increased time in range (between 70-180 mg/dl), but the risk of diabetic ketoacidosis (DKA) was noted to be substantially higher during all trials for the drug. The content of CRLs are rarely made public, but the reasoning behind the FDA’s decision is likely due in part to this increased risk of DKA.

Zynquista would have been the first medication of its kind approved for use in Type 1 diabetes. The only two drugs previously approved for use in T1D to lower blood sugar are insulin and pramlintide — both injectable.

It remains to be seen if Zynquista will be approved for people living with T1D in Europe, but the preliminary recommendations from the Committee for Medicinal Products for Human Use (CHMP) in Europe were considerably more positive than the recommendations from the FDA Advisory Committee in the U. S.

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Thank you for keeping us updated on all the news Mila! I know I’ve seen SGLT-1 and -2 drugs discussed here before (by some Type 1s), and my doctor has brought it up as a possibility with me as well (off-label). I’ve not heard about the increased risk of DKA with these drugs, though.

Does anyone here know why these drugs increase risk of DKA, and has anyone had personal experience (good or bad) as an IDD and taking these orals?

I’m not sure about the mechanisms behind the DKA risk. I think part of it is that it can artificially lower your blood sugar to near-normal even when you do not have enough insulin on board. And I think another part is that it lowers the amount of insulin you need and sometimes can lower it too much to a point where you have too little in your system.

I took Forxiga for about six weeks several years ago. My endocrinologist asked me to check ketones daily (I did so once or twice a day) and was also monitoring my blood ketone levels with lab tests every six weeks, I believe. Several times I ended up with high ketone levels and feeling a bit unwell and had to drink a ton of water and take extra insulin to get rid of them. (I was not eating a low-carb diet at the time; I chose to stop the low-carb diet before starting the medication because I was not comfortable with the risk fo always having ketones and therefore losing both the clues of high blood sugar and high ketones to indicate a problem might be developing, especially being on a pump prone to site failures.) The Forxiga was great for my blood sugar, but I ended up having to discontinue it due to unrelated side effects.

Documentation from the FDA Advisory Committee

What is “SH” on page 41 of the pdf?

severe hypoglycemia (SH)

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The key detail here is the BG level. SGLT inhibitors mask high BGs by causing most of it to be peed out.

I never liked SGLT inhibitors. IMO they are a cheap way to make it seem like you have good control, when actually you don’t. I suppose they are a great option for truly brittle diabetics whose BG just spikes no matter what. Otherwise though I think they do more harm than good.

Now, why can they lead to DKA? It’s because high BG’s can be a warning sign for DKA. High BG is not the cause of DKA (high blood acidity due to extremely high concentration of fatty acids in the blood is), but it is a side effect. If you are in DKA, or approaching DKA, you typically notice it early because of the high BG. Enter the SGLT-inhibitor. Now even though you are approaching DKA, you don’t notice it in the BG levels, because you get rid of most of the high BG through urination. There are no warning signs until it gets so bad that you develop other symptoms. Result: “euglycemic” DKA (I put euglycemic in quotes because actually you just got rid of most of the BG in the toilet).

I have mixed feelings about SGLT-inhibitors for type 1 diabetics. On one hand, as said, there are those with brittle diabetes who would greatly benefit from it. On the other hand, I see a real danger in that lazy / incompetent endos (or maybe even GPs) don’t even bother helping the diabetic adjust the BG treatment and just brush them off with a prescription for SGLT-inhibitors.

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Thanks for that explanation regarding DKA issues with Zynquista. I was trying to figure out why that would be the case. You explained it very well.