The Dangerous Consequences of Rushing Risky Drugs to Market

Both drugs are manufactured by AstraZeneca and contain the active ingredient saxagliptin. Kombiglyze XR works differently than Onglyza as it also contains metformin, an active substance that improves how the human body handles insulin. The drugs were approved - in 2009 and 2010, respectively - by the U.S. Food and Drug Administration (FDA).

In December 2008, before Onglyza was first released on the market, the FDA issued testing guidance to the pharmaceutical industry that was setting different expectations for the development of drugs for type 2 diabetes. This guidance mandated long-term cardiovascular outcomes trials for safety by calling for an expanded scope of research necessary for the approval of drugs similar to Onglyza.

Why was the guidance necessary? One of the primary health dangers of type 2 diabetes is that it greatly increases the risk of heart disease and stroke. Therefore, the FDA wanted to make sure that antidiabetes drugs did not increase cardiovascular risks even further.

However, because studies take time and time delay profits, AstraZeneca ignored the new FDA guidance and opted to perform the cardiovascular safety testing after Onglyza was released.

 After its release on the market, Onglyza became a very popular medication in the United States because it does provide some symptom resolution and because it does not cause weight gain, as many other glucose regulators do. So, at one time, both drugs were considered promising front-line options in the fight against diabetes.

But research also uncovered problematic risks with these medications. The active ingredient saxagliptin's main role is alerting the pancreas to produce insulin. This insulin boost blocks the liver from producing sugar. However, it appears that its effect on the body can also cause a rise in arterial blood pressure and heart rate through an increase in epinephrine levels.

Metformin, the second active ingredient in Kombiglyze XR, helps decrease sugar production in the liver and sugar absorption by the intestines, improving diabetics’ response to their own insulin. But the drug was also considered a contraindication in heart failure patients because it has been connected with lactic acidosis, a potentially lethal condition.

Onglyza and Kombiglyze XR were on the market for nearly five years by the time AstraZeneca finally completed the recommended studies to determine if the drugs increased the risks of cardiac injury.

The results of cardiovascular safety testing were published in 2013 in the New England Journal of Medicine (NEJM) and showed that saxagliptin created a significantly increased risk of heart failure. The article outlined the outcomes of the large, randomized review of more than 16,000 patients over 2 to 3 years.

Of these, more than 1,200 patients taking Onglyza reported a major cardiovascular event. This may have included possibly fatal heart attacks, strokes, or deep thrombotic events. The study indicated that diabetics taking Onglyza face a higher risk (27%) of hospitalization for heart failure as well as an overall increased risk of all-cause mortality than those not taking the drug.

That is why the results of this testing prompted the FDA to issue a safety communication in February 2014 on a possible link between Onglyza and heart failure.

In 2015, an FDA advisory committee discussed and voted on further action. The majority of the committee voted in favor of adding heart failure warnings to the saxagliptin labeling. Yet AstraZeneca ignored the FDA advice and continued to market Onglyza and Kombiglyze XR without adding any warning about heart failure risks. In 2016, the FDA issued its official statement calling for additional warnings about the risk of heart failure on the drug’s packaging.

And the research was only at the beginning, along with legal action against AstraZeneca, the drugs’ manufacturer. According to a 2019 study published in Diabetes Care, saxagliptin is also associated with an increased risk for pancreatitis and pancreatic cancer in patients with newly diagnosed type 2 diabetes. Data obtained from a total of 33,208 patients showed that an intake of saxagliptin was associated with a 1.27 significantly higher risk for pancreatitis and a 1.50 higher risk for pancreatic cancer.

Many patients now allege that AstraZeneca and former partner Bristol-Myers Squibb concealed information linking saxagliptin to an increased risk of heart failure, failed to properly warn doctors and patients, and did not perform adequate clinical studies to determine the extent of cardiovascular risk, despite the 2008 FDA recommendation.

The company's actions led to tragic results and, as such, there are now at least 256 active Onglyza and Kombiglyze XR product liability cases. In February 2018, all the lawsuits were centralized as part of a multidistrict litigation (a legal procedure designed to speed the process of handling complex cases with common questions of fact and law) in federal court in Kentucky.

The litigation is ongoing and there have not been any publicly announced settlements or jury verdicts. Also, there hasn't been a recall of Onglyza or Kombiglyze XR. As the litigation is in its early stages, the lack of settlements is not unusual, but it has been delayed by the judge's decision to first focus on whether plaintiffs can prove the link between the drugs and heart failure.

However, the purposes of centralization are coordinated discovery and pretrial proceedings and possibly greater financial compensation awards for plaintiffs.

People have reason to be concerned about the safety of Onglyza and Kombiglyze use, as well as the actions of drug manufacturers who rush products to market, thus ignoring and suppressing critical research findings.