Study results presented Monday at the European Society of Cardiology (ESC) congress showed that diabetes therapies in the DPP-4 inhibitor class do not increase the risk of myocardial infarction (MI). However the data from the two cardiovascular (CV) outcomes trials, which were also published in the NEJM, suggest that the drugs may be linked to an increase in the risk of hospitalisation due to heart failure.
One study, named SAVOR-TIMI 53, randomised 16 492 adults with type 2 diabetes who were at high risk for a CV event to receive AstraZeneca and Bristol-Myers Squibb's Onglyza (saxagliptin) or placebo. The second trial, called EXAMINE, randomised 5380 patients with type 2 diabetes and a recent acute coronary syndrome to receive Takeda's Nesina (alogliptin) or placebo.
AstraZeneca and Bristol-Myers Squibb previously reported top-line results from the SAVOR-TIMI 53 trial, demonstrating that Onglyza failed to show superiority on the composite primary endpoint of CV death, non-fatal MI or non-fatal ischaemic stroke. According to further data released Monday, the primary endpoint occurred in 7.3 percent of patients given Onglyza, compared to 7.2 percent for those in the placebo group. In addition, a secondary endpoint of the composite of CV death, MI, stroke, hospitalisation for unstable angina, coronary revascularisation or heart failure occurred in 12.8 percent of patients receiving Onglyza, versus 12.4 percent in the placebo group.
Meanwhile, in the EXAMINE trial, the main goal of the primary composite endpoint of CV death, non-fatal MI and non-fatal stroke occurred in 11.3 percent of patients given Nesina, compared to 11.8 percent of those in the placebo group. Takeda noted that the study met its main goal, showing non-inferiority of Nesina compared to placebo on this measure.
However, results of the SAVOR-TIMI 53 trial also showed that hospitalisation for heart failure occurred in 3.5 percent of patients treated with Onglyza, which was at a greater rate than the 2.8 percent for those in the placebo group. Co-principal investigator Deepak Bhatt, who called the heart failure finding "unexpected," suggested that the issue was very likely a class effect common to all DPP-4 inhibitors, adding that it had probably not shown up in the Nesina trial because it was smaller. He said that further examination is needed to verify the findings and understand which patients might be susceptible to heart failure.
"What we need to do and, in fact what we're doing, is really trying to drill down on that and see exactly who might be at risk for heart failure," remarked Bhatt. AstraZeneca's head of global medicines development Briggs Morrison noted that the overall results of the SAVOR-TIMI 53 trial were reassuring and the small increase in heart failure hospitalisations did not change the risk profile of the drug.
Commenting on the data, Citigroup analyst Andrew Baum said the results would not ameliorate growing pressures on the DPP-4 drug class in terms of gaining reimbursement and achieving wider use. He predicts that Onglyza, which had sales of $709 million in 2012, could generate revenue of nearly $2.5 billion in 2018. Merck & Co.'s DPP-4 inhibitor Januvia (sitagliptin) has global sales of around $5 billion, and results from a CV outcomes study on the drug are expected next year.
Some physicians had expected Onglyza and Nesina to reduce heart risks in the two studies. However, ESC spokesman Heinz Drexel suggested that it was "not very logical" to think that lowering blood glucose levels alone would translate into a reduction in risk of MI. In an accompanying editorial published in the NEJM, William Hiatt, Sanjay Kaul and Robert Smith noted that "it is disappointing...that neither intensive glycaemic control nor the use of specific diabetes medications is associated with any suggestion of cardiovascular benefit." They suggested that the FDA should reconsider its requirement that all diabetes drugs be forced to demonstrate their CV safety. Kaul added that the FDA also needs to think about a new way of assessing such drugs, suggesting that rather than using HbA1c as a marker, it is time "to consider a patient-oriented clinical outcome of benefit," such as prevention of kidney failure or blindness.
For related analysis, see ViewPoints: AstraZeneca/Bristol-Myers Squibb SAVOR results – missed opportunity or sigh of relief?
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