Why did FDA reject sotagliflozin? Safety concerns outweighing benefits in Type 1 diabetes

In late 2024, the FDA's advisory committee delivered an 11-3 vote against approving sotagliflozin (brand name Zynquista) for type 1 diabetes patients with chronic kidney disease. This decision marked the second major setback for the drug in this indication, as the FDA rejected sotagliflozin once again over persistent and unmitigated concerns about a heightened risk of diabetic ketoacidosis (DKA).

Quick Summary

The FDA repeatedly rejected sotagliflozin's application for type 1 diabetes due to significant safety concerns regarding diabetic ketoacidosis. Despite effective risk mitigation strategies being proposed, the increased DKA risk outweighed its glycemic benefits. This contrasts with its 2023 approval for heart failure under the brand name Inpefa.

Key Points

• Initial Rejection in 2019: The FDA first rejected sotagliflozin for type 1 diabetes (T1D) after an 8-8 advisory committee vote raised concerns about an increased risk of diabetic ketoacidosis (DKA).

• Persistent DKA Risk: The primary reason for both rejections was the unacceptable and elevated risk of DKA, a life-threatening complication, particularly in T1D patients.

• Failed Resubmission in 2024: A resubmission for a narrower patient population (T1D with chronic kidney disease) was also rejected in December 2024, following an 11-3 advisory committee vote, as the risk of DKA was still deemed too high.

• Inadequate Risk Mitigation: The FDA was not convinced that the proposed risk evaluation and mitigation strategies were sufficient to ensure patient safety for the T1D indication.

• Approval for Heart Failure: Sotagliflozin was approved by the FDA in 2023 under the brand name Inpefa, but for heart failure and related cardiovascular risks in patients with or without type 2 diabetes, based on a separate set of clinical trial data.

• Indication-Specific Decision: The contrasting outcomes for T1D and heart failure demonstrate that the FDA's approval process is indication-specific and based on the unique benefit-risk profile for each patient population.

The Initial 2019 Rejection: An Elevated DKA Risk

Sotagliflozin, a dual SGLT1 and SGLT2 inhibitor, was initially reviewed by the FDA in 2019 as Zynquista for type 1 diabetes (T1D). While clinical trials showed benefits like improved glycemic control and weight loss, a significant concern was an elevated risk of diabetic ketoacidosis (DKA). Despite an 8-8 advisory committee vote, the FDA issued a Complete Response Letter (CRL) in March 2019, stating that the DKA risk outweighed the benefits, even with proposed mitigation strategies. An appeal was later denied.

Sotagliflozin's Mechanism and the DKA Concern

Sotagliflozin inhibits both SGLT1 and SGLT2 proteins, which regulate glucose. In T1D patients, this mechanism can increase the risk of euglycemic DKA, where DKA occurs with normal blood glucose levels, making it harder to detect. Trials showed a higher DKA rate compared to placebo, and the FDA and advisory panels were not convinced that proposed monitoring could adequately manage this risk in real-world settings.

The 2024 Resubmission and Second Rejection

Lexicon resubmitted for a narrower population of adults with T1D and chronic kidney disease (CKD), including new data. However, in October 2024, the FDA advisory committee voted 11-3 against approval, again concluding the DKA risks outweighed the benefits. Concerns remained about the data and managing DKA in CKD patients. Following this, Lexicon halted development for the T1D indication, and the FDA issued a second CRL in December 2024.

A Different Outcome: FDA Approval for Heart Failure (Inpefa)

In contrast to the T1D outcome, sotagliflozin was approved in May 2023 as Inpefa for heart failure. This approval was based on trials like SOLOIST-WHF and SCORED, which showed significant reductions in cardiovascular events, demonstrating a clear benefit-risk profile for this population that differed from T1D.

Comparing the Rejected T1D and Approved Heart Failure Applications

The FDA reviewed sotagliflozin differently for Type 1 Diabetes (T1D) and Heart Failure (HF) indications. For T1D, the application as Zynquista initially targeted a broader T1D population and later a subset with chronic kidney disease (CKD), primarily showing improved glycemic control but facing a significant risk of Diabetic Ketoacidosis (DKA). The FDA advisory committee votes were unfavorable, 8-8 and then 11-3 against approval, leading to rejection due to the DKA risk outweighing benefits. In contrast, the application for heart failure as Inpefa was approved in 2023 for adults with HF or Type 2 Diabetes, CKD, and CV risks. This approval was supported by trials like SOLOIST-WHF and SCORED, which demonstrated reductions in cardiovascular events, establishing a favorable benefit-risk profile for this population. Ultimately, development for the T1D indication was halted by Lexicon, while Inpefa is currently available for heart failure.

Conclusion: The Final Verdict and Future Considerations

The FDA's decision to reject sotagliflozin for type 1 diabetes hinged on an unfavorable benefit-risk assessment, primarily due to the persistent, unmitigated DKA risk. The proposed safety measures were not deemed sufficient for real-world T1D management. The successful approval for heart failure, based on strong cardiovascular benefit data, highlights the FDA's indication-specific review process. For the T1D community, the drug will not be available, with Lexicon shifting focus to other treatments.

Visit the FDA website for more information on approved medications.

Frequently Asked Questions

What is sotagliflozin and what does it treat?

Sotagliflozin is a dual inhibitor of the SGLT1 and SGLT2 proteins, which regulate glucose absorption. It is currently approved by the FDA under the brand name Inpefa to treat heart failure and related cardiovascular risks in adults with heart failure or with type 2 diabetes and chronic kidney disease.

Why was the risk of diabetic ketoacidosis (DKA) a major concern for T1D patients?

DKA is a serious complication more common in type 1 diabetes. Sotagliflozin's mechanism of action, which lowers blood glucose by inhibiting glucose reabsorption, can create conditions that increase the risk of DKA, including euglycemic DKA where blood sugar levels appear normal.

Did the FDA reject the drug for all diabetes indications?

No. The FDA specifically rejected sotagliflozin for use as an add-on therapy for type 1 diabetes. Its approval for certain heart failure patients includes those with type 2 diabetes and cardiovascular risk factors, as supported by different clinical trials.

What happened with the advisory committee votes for the T1D application?

For the initial 2019 application, the advisory committee was split with an 8-8 vote, leading to a rejection. For the 2024 resubmission, the vote was 11-3 against approval, leading to the second rejection for the T1D indication.

Was a risk mitigation strategy considered to address the DKA risk?

Yes, the manufacturer proposed a risk evaluation and mitigation strategy (REMS), including monitoring for ketones. However, the FDA concluded that these strategies were not sufficiently convincing or practical for real-world use to mitigate the unacceptable DKA risk.

Why was sotagliflozin successful for heart failure but not type 1 diabetes?

The heart failure approval was based on robust data from the SOLOIST-WHF and SCORED trials, which showed a clear and significant cardiovascular benefit that outweighed the risks in that specific patient population. The risk-benefit profile for T1D patients, with the prominent DKA risk, did not pass the same regulatory threshold.

What is the status of sotagliflozin development for type 1 diabetes?

Following the second rejection in December 2024, manufacturer Lexicon Pharmaceuticals discontinued the development and commercialization plans for sotagliflozin (Zynquista) for the type 1 diabetes indication.