Despite Concerns over Onglyza, FDA Keeps Going Back to the Trough

Washington, DCIn the accepted parlance of the pharmaceutical and medical industries, a drug is considered not unsafe for the intended patient if the benefits of the drug outweigh the risk. One can therefore assume that the US Food and Drug Administration (FDA) took this mantra to heart in 2009 when the federal regulator approved Onglyza (saxagliptin) in spite of reservations over potential saxagliptin side effects and the results of clinical trials associated with Onglyza conducted before the drug was approved.

Onglyza, a drug indicated for type 2 diabetes, was approved anyway. However the FDA nonetheless was sufficiently concerned to mandate that the manufacturers of Onglyza undertake a post-marketing study with a focus towards cardiovascular safety.

The results of that post-marketing study were released four years later and were not favorable. However, in the interim – and within a year of approving Onglyza for use in the US – the FDA also approved the Onglyza hybrid known as Kombiglyze XR, which is an extended-release combination of saxagliptin (Onglyza) and metformin, the latter one of the oldest medications to treat diabetes with an excellent safety profile when compared with other oral diabetic medications.

However, metformin carries its own basket of side effects. Industry observers note that patients taking Kombiglyze could experience Kombiglyze side effects that could potentially include adverse reactions from both saxagliptin (Onglyza) and metformin. Many patients have filed, or are considering a saxagliptin lawsuit claiming serious side effects. One plaintiff from New York – identified as Dino Cortina – claims that manufacturers AstraZeneca and Bristol-Myers Squibb Company failed to warn consumers and the medical community about the risks, amongst other allegations.

Remember that Onglyza was approved under a cloud in 2009, given that the FDA had reservations about clinical trial results, but approved saxagliptin anyway. The post-marketing study the manufacturers were mandated by the FDA to undertake was known as the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR) –Thrombolysis in Myocardial Infarction (TIMI) 53, and involved 16,492 study participants. Research was conducted from May, 2010 through December 2011, with the results published in the New England Journal of Medicine (NEJM) in 2013 – four years after Onglyza was approved and appeared on the market. The SAVOR-TIMI 53 study revealed that Onglyza did not contribute to saxagliptin heart attack. Researchers also did not find any evidence that saxagliptin presented any capabilities for protecting the heart, either.

However, the headline-grabber proved to be a 27 percent increased risk of hospitalization for heart failure, together with the potential for increased risk for “all-cause mortality.”

When the outcomes were revealed, one member of the FDA panel convened to study the results and suggested a response put forward a recommendation to pull Onglyza from the market entirely due to the potential for Onglyza heart attack. The panel, however, determined the best course of action was to leave saxagliptin on the market, but to mandate the inclusion of additional warnings.

This was done, with warnings speaking to the potential risks for heart failure and hospitalization on labels for both Onglyza and Kombiglyze XR. But over the ensuing years there have also been warnings added for increased risk of pancreatitis and pre-cancerous findings of the pancreas. The FDA also added warnings for the potential of severe – to the point of disabling – joint pain.

The results of the SAVOR-TIMI 53 study on the cardiovascular system, together with other studies into Onglyza side effects involving the pancreas and the various warnings the FDA has mandated to warrant keeping saxagliptin on the market, no doubt serves as a reminder to the FDA of its unease about approving saxagliptin in 2009 amidst concerns over clinical trial data.

That has not stopped the FDA from moving Onglyza forward yet again. In February of this year, the federal regulator approved a new oral type 2 diabetes drug that combines saxagliptin (Onglyza) with dapagliflozin (Farxiga).

The new drug is known as Qtern, and will make saxagliptin available to a new cohort of patients for whom this new medication is indicated. Will we see a new round of saxagliptin side effects lawsuits as a result?

Time will tell.