AstraZeneca has announced that the U.S. Food and Drug administration rejected an application for approval of a new type-2 diabetes drug that combines the active ingredients in Farxiga and Onglyza, saying the federal agency needs more clinical data to support the application.

Farxiga is a new generation of diabetes drugs known as sodium glucose cotransporter-2 (SGLT-2) inhibitors. Other drugs in the class include Invokamet, Jardiance, Xigduo XR and Glyxambi.

Onglyza is DPP-4 inhibitor. Both drugs are used along with diet and exercise to lower blood sugar levels in adults with type-2 diabetes.

The FDA’s rejection of AstraZeneca’s application comes nearly six months after an advisory committee for the agency voted in April to recommend stronger warnings about the potential risk of heart failure from Onglyza side effects. The FDA launched an investigation into Onglyza heart risks last year, following a study published by the New England Journal of Medicine in 2013.

On May 15, the FDA announced it was investigating a growing number of reports linking Farxiga and other SGLT-2 inhibitors to diabetic ketoacidosis.

AstraZeneca did not state the specific reasons for the rejection of the new combination drug, but said the rejection was not final.

“This includes clinical trial data from ongoing or completed studies and may require information from new studies,” the press release states. “AstraZeneca will work closely with the FDA to determine the appropriate next steps for the NDA (New Drug Application) and remains committed to the development of the saxagliptin/dapagliflozin fixed-dose combination.”

AstraZeneca had previously estimated that the new combination drug could have brought in as much as $3 billion in sales.

Onglyza Side Effects Under Investigation

In February 2014, the FDA demanded additional data from the makers of saxagliptin (marketed as Onglyza and Kombiglyze XR), over concerns of heart failure allegedly linked to the diabetes medication. This formed part of a parade of scrutiny from the FDA on the subject.

In February 2013, the FDA announced that the agency had requested more clinical data to evaluate the risk of heart failure in diabetes patients taking saxagliptin. The announcement came in response to a New England Journal of Medicine article published in October 2013.

The NEJM article found an increased risk of heart failure. Curiously, the study was looking into other types of heart problems, specifically ischemic events, or events where blood clots block the flow of blood to critical tissues, like strokes. While the NEJM study found no evidence of ischemic events, researchers did note that patients taking saxagliptin had an increased rate of hospitalization of heart failure, a condition wherein patients’ hearts are not pumping enough blood for them to function.

Researchers couched their results, saying a study like this could not prove causation, but concluded the evidence was strong enough to warrant further attention to the subject. The FDA’s announcement indicated that the agency had taken interest, and demanded clinical data from the drug’s manufacturers by March 2013.

In April 2015, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee convened to discus the matter further, based on clinical data. According to the minutes of the meeting, the FDA held a vote on the subject of Onglyza’s labeling and heart failure concerns. During the vote, 14 of the committee’s 15 members voted to add warnings to the labeling of Onglyza to advise patients of the risk of heart failure like those described in the NEJM study. The last member of the committee actually voted to completely withdraw Onglyza from the market.