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BOSTON -- The novel GLP-1 drug lixisenatide (Lyxumia) doesn't reduce cardiovascular events compared with other diabetes regimens but doesn't raise them either, the FDA-mandated ELIXA safety trial showed.

The risk of between patients on the drug versus placebo as part of their antidiabetic regimen managed to the same glycemic target (rate 13.4% versus 13.2%, hazard ratio 1.02, 95% confidence interval 0.89-1.17).

That met the FDA standard for ruling out cardiovascular harm but didn't meet the primary endpoint seeking superiority of lixisenatide.

All components as well as overall mortality also turned out neutral, as were analyses by subgroup and when adding in heart failure hospitalizations, , a cardiologist at Brigham and Women's Hospital in Boston, and colleagues reported here at the American Diabetes Association meeting.

"We are well within that safety range but on the other hand we can't say that randomization to lixisenatide improved prognosis of these high-risk patients," he told reporters at a press conference. "This should provide physicians and patients reassurance for this adjunctive therapy to better control their glucose status."

The findings were followed by similarly neutral results from the TECOS cardiovascular outcomes trial for the DPP-4 drug sitagliptin (Januvia) presented at the conference.

Drugmaker Sanofi announced plans to resubmit lixisenatide for FDA approval later this year based on ELIXA.

Other GLP-1 receptor agonists' answer to the FDA requirement for cardiovascular safety trials for all new type 2 diabetes drugs (instituted in 2008 in the wake of the rosiglitazone [Avandia] cardiovascular risk scare) are expected to report outcomes from 2016 to 2019.

No Surprise

Study discussant , director of Yale's Diabetes Center, agreed that the findings were reassuring and suggested that these first cardiovascular outcome data for a GLP-1 receptor agonist increase the likelihood that cardiovascular outcomes trials will come out similarly neutral for the rest of the class.

"It would be very optimistic that any of these trials are going to show benefit," he told reporters after chairing the press conference. "That's because [glucose control] is a tiny piece of the atherosclerotic puzzle."

Even if there was a heart benefit, the 2- to 3-year follow-up of these trials certainly wouldn't be enough to find it, he said.

Trials that have ended up showing a cardiovascular benefit from better glucose control have sometimes found it after 5 to 7 year study but more often over 10 to 20 years of follow-up, he noted.

"It doesn't mean that this is a useless product," Inzucchi said. "We use these products to lower long-term microvascular risk."

"Any way we can reduce glucose will," he added, "over a 5 or 10 year period, have a substantive impact on patient's lives in terms of reduction of microvascular risk -- retinopathy, nephropathy, and neuropathy."

Modest Advantages

, physicians' discretion of additional non-incretin-based antidiabetic medications was meant to target the the same typically 7% to 8% hemoglobin A1c range for the 6,068 type 2 diabetes patients randomized.

But glycemic control still came out slightly better with lixisenatide (mean post-baseline difference -0.27%, 95% CI -0.32 to -0.22).

Lixisenatide also had modest but significant advantages for:

• Slowing the increase in urinary albumin to creatinine ratio (24% versus 34% up from baseline to month 24)
• Weight (0.7 kg less than with placebo)
• Blood pressure (0.8 mm Hg versus placebo)

Some Disadvantages, Too

The drug did carry more adverse events overall, especially nausea and vomiting.

And it significantly increased heart rate compared with placebo by a mean of 0.4 beats per minute more over baseline, which "when you talk to cardiologists is not good for the ischemic heart," Inzucchi noted.

Most participants had myocardial infarction as their qualifying acute coronary syndrome event for entry into the trial rather than unstable angina, which accounted for only about 17% in both groups. The duration of diabetes averaged a little over 9 years in both groups.

There were no signals for pancreatitis, pancreatic cancer, other cancers, or heart failure, around which questions have been raised for fellow incretin-based diabetes drugs, the DPP-4s.

That aspect was also reassuring, although the relatively short follow-up might not have provided enough time to look at malignancy risk either, cautioned , of the University of Colorado Denver and a past president of the AHA.

But with overall little advantage to lixisenatide, it's hard to see a rationale for spending the amount this class of drugs has been costing compared with other regimens that seem to work roughly as well, Inzucchi suggested.

"The cost of this drug to prevent events is infinite," he said. Even in terms of the cost to lower glucose levels, he projected, "it's extremely expensive.

"You can purchase 10 years of a generic sulfonylurea with 1 month of a top-dose GLP-1 agonist. ... For glucose control, the justification of the cost of these medications has to be based not only on their effects on complications but ease of use and quality of life and all that."

GLP-1 drugs are often used clinically to enhance weight reduction, Eckel noted.

"That may be worth the expense," he told MedPage Today. "The lack of benefit in this outcomes study with lixisenatide doesn't deter me from using any GLP-1 agonist if I want to target A1c with weight reduction."

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