DKA concerns remain paramount in FDA’s denial of sotagliflozin for type 1 diabetes

January 13, 2025
8 min read
Key takeaways:
- For the second time since 2019, the FDA in December decided not to approve sotagliflozin for adults with type 1 diabetes.
- Lexicon Pharmaceuticals has halted all planned commercial activities for Zynquista.
For the second time since 2019, the oral SGLT1 and SGLT2 dual inhibitor sotagliflozin has been denied FDA approval for adults with type 1 diabetes, with elevated risk for diabetic ketoacidosis being a primary concern.
Lexicon Pharmaceuticals acknowledged the receipt of an FDA complete response letter for sotagliflozin (Zynquista, Lexicon) in a press release on Dec. 20. The company had filed a new drug application for sotagliflozin to improve glucose control as an adjunct to insulin for adults with type 1 diabetes and chronic kidney disease in July.

In its Dec. 20 press release, Lexicon described the complete response letter as an “expected communication” after the FDA Endocrinologic and Metabolic Drugs Advisory Committee recommended against approving sotagliflozin on Oct. 31 in a 3-11 vote.
After the FDA committee’s decision, Lexicon announced in a press release on Nov. 22 it would halt all planned commercial activities for sotagliflozin as part of a strategic restructuring to eliminate commercial operations and focus all its resources on its clinical development pipeline.
“We are sincerely grateful to the patients and physicians who participated in our Zynquista clinical trials, and the broader diabetes community who strongly advocated for Zynquista’s approval,” Mike Exton, PhD, CEO and director of Lexicon, said in a press release. “Although this was not our desired outcome for sotagliflozin in this indication, we remain steadfast in our commitment to advancing our clinical pipeline, including our near-term focus on LX9211 for diabetic neuropathic pain with top-line data from our PROGRESS phase 2b study anticipated in first quarter of 2025, and pursuing innovations that we believe can profoundly benefit patients.”
The FDA decision and Lexicon Pharmaceuticals’ announcement was a disappointment for several health care professionals, including Steven V. Edelman, MD, professor of medicine at University of California, San Diego; founder and director of Taking Control Of Your Diabetes and a Healio | Endocrine Today Editorial Board Member. Edelman, who presented as an outside expert during the FDA committee meeting, said several SGLT inhibitors have data available showing cardiovascular and renal benefits for adults with type 1 diabetes, including canagliflozin (Invokana, Janssen), dapagliflozin (Farxiga, AstraZeneca) and empagliflozin (Jardiance, Boehringer Ingelheim/Eli Lilly). However, Edelman noted Lexicon’s presentation to the FDA lacked data on the potential renal benefits of sotagliflozin in type 1 diabetes.

Steven V. Edelman
“[Lexicon] just did a subanalysis of their [previous] studies, and they pulled out patients who had [CKD] in those studies,” Edelman told Healio. “They didn’t have any new data, and they didn’t have a lot of data, which is what the FDA was looking for.”
The concerns about an increased risk for DKA were warranted, according to Anne L. Peters, MD, diabetologist and professor of clinical medicine at the USC Keck School of Medicine, and a Healio | Endocrine Today Editorial Board Member. Peters said SGLT inhibitors as a class tend to increase DKA risk for people with type 1 diabetes and she expressed uncertainty as to whether any risk mitigation plans could be effective in real-world clinics.
“In an ideal world, we’d have sotagliflozin available because it’s an easy tool,” Peters said. “We know how well it works. We know that it works for heart failure and CKD in people without diabetes as well as those with type 2 diabetes. There are many nonglycemic benefits. In an ideal world, I’d have it available, I just have to have it safe.”
Kevin M. Pantalone, DO, ECNU, FACE, professor of medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, director of diabetes initiatives and staff endocrinologist in the department of endocrinology at Cleveland Clinic, said he lamented the FDA’s decision because of the lack of non-insulin therapies available for people with type 1 diabetes, adding that sotagliflozin could have filled a much-needed gap.
“These patients have limited options,” Pantalone told Healio. “We make a big deal about only half of type 2 diabetes patients being at their HbA1c goal. If you look at type 1 diabetes, it’s less than one-third of patients meeting their target, and it’s because they don’t have many options.”
DKA risk sparks discussion
Sotagliflozin was approved by the FDA in 2023 to reduce risk for CV death, hospitalization for heart failure and urgent heart failure visit in patients with heart failure or type 2 diabetes, CKD and other CV risk factors. However, the medication has twice come up short of receiving FDA approval for the treatment of type 1 diabetes due to the agency’s concern over increased risk for DKA.
As Healio previously reported in January 2019, the FDA Endocrinologic and Metabolic Drugs Advisory Committee had a split, 8-8 vote, to recommend sotagliflozin for approval in adults with type 1 diabetes. During that meeting, some committee members cited safety data from the inTandem3 trial, in which adults with type 1 diabetes were randomly assigned to once-daily sotagliflozin 400 mg as an adjunct to any insulin therapy or placebo for 24 weeks. During the trial, DKA occurred in 3% of adults receiving sotagliflozin compared with 0.6% of adults receiving placebo. In March 2019, the FDA opted not to approve sotagliflozin when it issued a complete response letter.
Concerns over DKA were again brought up again when the FDA Endocrinologic and Metabolic Drugs Advisory Committee considered sotagliflozin for adults with type 1 diabetes and CKD in October, with the risk for DKA cited as a concern for many of the committee members voting against approval.

Kevin M. Pantalone
Pantalone said he understands there was increased risk for DKA in the inTANDEM3 trial, but he noted it was conducted at a time when fewer people with type 1 diabetes were using insulin pumps and closed-loop insulin delivery systems. He said he would have liked to see new safety data that better reflect the current type 1 diabetes population and technologies being used to manage their condition.
“I feel clinicians are more understanding today of the need to discuss with patients about euglycemic DKA and to check their ketones,” Pantalone said.
During its 2019 hearing, several members of the FDA panel stated a risk evaluation and mitigation strategy was needed to manage the increased DKA risk observed during inTANDEM3. As Healio previously reported, in a briefing document before the 2024 hearing, FDA staff wrote that various risk mitigation strategies were proposed, but their effectiveness was not demonstrated in clinical trials.
In disagreeing with the FDA’s statement, Edelman said Lexicon had a risk mitigation strategy centered on educating both health care professionals and people with type 1 diabetes about DKA that could be beneficial for all stakeholders.
“If you suspect DKA, there’s some really simple things you do: You drink a lot of fluids, you take insulin, you take carbohydrates.” Edelman said.
Peters said she supports the potential approval of new therapies for type 1 diabetes, but also understood the FDA’s decision from a safety perspective and emphasized how risk mitigation strategies are not necessarily feasible for all patients.
“When I think of these FDA approvals, I think about my under-resourced patients who don’t have access to easy medical care, who don’t receive ketone test strips as a part of their treatment,” Peters told Healio. “To be impactful, this medication needs to be able to be used safely in those people.”
Peters said she prefers a DKA risk mitigation plan with sotagliflozin that includes continuous ketone monitoring and access to long-acting insulin. However, she acknowledged such a plan may feel cumbersome for some people with type 1 diabetes.
“We’d be asking them to adhere to continuous ketone monitoring and have a backup plan for fingerstick or urine ketone testing, because it is often when technology fails that issues develop,” Peters said. “I find that my patients on pumps and automated insulin delivery systems are the ones who most often go into DKA on SGLT2 inhibitors, and no matter how much I educate them this has still happened. I am not yet convinced that we yet have a protocol that is effective enough to fully mitigate the risk of DKA in people with type 1 diabetes.”
While Pantalone expressed disappointment with the decision, he also understood why the FDA opted not to approve sotagliflozin for type 1 diabetes.
“The FDA’s concerns regarding patient safety and risk mitigation strategies being potentially ineffective and challenging to implement in the real-world setting were valid,” Pantalone said. “But I think these issues could have been addressed through shared decision making on an individualized basis.”
Other therapeutic options
Sotagliflozin is not the first SGLT inhibitor to fall short of FDA approval for type 1 diabetes. As Healio previously reported, the FDA opted to not approve dapagliflozin in 2019 and empagliflozin in 2020 as an adjunct to insulin for type 1 diabetes.
The number of FDA-approved options for treating type 1 diabetes outside of insulin is very small. Pantalone said pramlintide (Symlin, AstraZeneca) is the only non-insulin FDA-approved medication for type 1 diabetes and it is used by very few patients. The FDA also approved a pancreatic islet cellular therapy in 2023, but the therapy was indicated specifically for adults with type 1 diabetes struggling to achieve their target HbA1c due to severe hypoglycemia.
There are several factors contributing to the lack of FDA-approved therapies for type 1 diabetes. Edelman said the small number of people with the condition makes it difficult and expensive for pharmaceutical companies to conduct large randomized controlled trials for drugs. Pantalone said he believes that the mindset of pharmaceutical companies on type 1 diabetes treatment is also a contributing factor.
“There’s the notion that type 1 diabetes is an insulin deficiency disease and that’s what patients require,” Pantalone said. “We have insulin. We have technology. That is the bridge to a true biological cure. So maybe long term, they just don’t see ancillary therapies as having a place.”
Despite the lack of an indication, Edelman and Pantalone both acknowledged health care professionals prescribe SGLT inhibitors off-label for people with type 1 diabetes. Edelman said multiple studies that have found CV and renal benefits with SGLT inhibitors included some adults with type 1 diabetes, and Pantalone said SGLT inhibitors can also provide glycemic benefits.
“SGLT inhibitors help to improve time in range,” Pantalone said. “Glucose variability is something that drives patients crazy and helping to improve time in range is becoming ever more important.”
Peters said some health care professionals, prescribe SGLT inhibitors off-label for type 1 diabetes, including herself in the past. Peters said has been hesitant to do so recently due to both the increased risk for DKA during the COVID-19 pandemic and the potential benefits other classes of medications may provide.
“I think SGLT inhibitors are really good drugs,” Peters said. “But I think there may be equivalent agents that we can use in people with type 1 diabetes to slow progression of nephropathy, as shown in people with type 2 diabetes as well as obesity. In some of my patients, basic treatment such as controlling BP and using ACE inhibitors or angiotensin receptor blockers still need to be implemented.”
GLP-1 based medications such as semaglutide (Ozempic/Wegovy, Novo Nordisk) and tirzepatide (Mounjaro/Zepbound, Eli Lilly) are not specifically approved by the FDA for adults with type 1 diabetes. However, data from the FLOW study showed semaglutide could provide renal benefits for adults with type 2 diabetes and CKD, and multiple studies have found tirzepatide reduces HbA1c and body weight for adults with type 1 diabetes using the medication off-label.
“All of the attention has been on the new drugs for type 2 diabetes, but there are a lot of people, including myself, that think SGLT inhibitors as well as GLP-1 agonists should be approved in type 1 diabetes,” Edelman said.
In addition to GLP-1 based drugs, a phase 3 trial is ongoing to assess treatment with finerenone (Kerendia, Bayer) in people with type 1 diabetes and CKD. Pantalone said finerenone could be a promising therapeutic option for the type 1 diabetes population which have CKD.
“People with type 1 diabetes are living longer,” Pantalone said. “These patients are living long enough to develop these cardiometabolic complications. … As many with type 1 diabetes get older, become more insulin resistant, and develop obesity, they tend to develop physiology that is more like type 2 diabetes. You could anticipate to see very similar benefits.”
References:
Garg SK, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1708337.
Lexicon announces receipt of complete response letter for Zynquista (sotagliflozin). Published Dec. 20, 2024. Accessed Dec. 23, 2024.
Lexicon to reposition as clinical development-focused company following regulatory update from FDA. Published Nov. 22, 2024. Accessed Dec. 23, 2024.
For more information:
Steven V. Edelman, MD, can be reached at [email protected].
Kevin M. Pantalone, DO, ECNU, FACE, can be reached at [email protected]. LinkedIn: @KevinPantalone
Anne L. Peters, MD, can be reached at [email protected].
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