乌鸦传媒

NEW ORLEANS -- Liraglutide (Victoza) was linked to a reduction of major cardiovascular events and all-cause mortality, becoming only the second type 2 diabetes drug to show cardiovascular benefit in a postmarketing trial.

The long-acting glucagon-like peptide-1 analogue (GLP-1) was associated with a 13% relative risk reduction in the composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke (P=0.01) in the 3-year LEADER trial, according to , of the University of Toronto.

The drug also yielded a 15% reduction in all-cause mortality (P=0.02) and a 22% reduction in cardiovascular death (P=0.007) during follow-up.

The absolute difference in outcome for preventing a coronary event was 1.9%, and the number of patients who would need to be treated to prevent one coronary event over a 3-year period was 66. The number to treat to prevent one death was 98.

The LEADER results were published online in the simultaneously with its presentation at the American Diabetes Association meeting in New Orleans.

Among the secondary endpoints in the study, treatment with liraglutide was associated with a 22% reduction in the time to a first renal event (HR 0.79, 95% CI 0.67-0.92), which was significant. There was also a nonsignificant 15% increase in the time to first eye event (HR 1.15, 95% CI 0.87-1.52), the researchers reported.

As moderator of the press conference, , a member of the American Diabetes Association Board of Directors and professor of medicine at the University of Colorado School of Medicine in Aurora, said, "LEADER is a complicated study but it may have an impact on practice."

He told 乌鸦传媒 that liraglutide may fit into the treatment algorithm when doctors consider what to prescribe for patients who can't reach their HbA1c goals on metformin, the generally accepted first-line treatment. "But now with EMPA-REG, published a year ago, and now with LEADER we have to think beyond metformin as to what that second drug of choice might be. With LEADER we already have a hint that there may be another drug in this class that appears to be beneficial," Eckel said.

"I think, ultimately, validation of these results is needed for this to change practice. I think that if my patients needs to lose weight, I am going to think in terms of a drug that causes weight loss in addition to controlling glycemia. I would like to see second and third trials with both of these drugs -- liraglutide and empagliflozin," he added.

Eckel suggested that the results in LEADER indicate that the benefit may come from the overall ability of the treatment to affect multiple factors. "LEADER gives me a hint of a lot of modifiable risk factors for cardiovascular disease -- a little bit lower systolic blood pressure, lower waist circumference, lower body weight -- lots of things related to cardiovascular disease risk," he explained. "Everything is sort of changing modestly in the right direction. Is it the modest HbA1c reduction? Or is it some composite advantage and everything is additive to something else?"

However, Eckel said that the high number to treat takes some wind out of LEADERS's sails. "We rather crudely use 50 as the number to treat as the goal for many interventions, so the issue that comes up next with liraglutide is one of cost," he said. "These drugs are still expensive. It's a challenge to push these drugs in the absence of adequate insurance coverage. I am not going to make somebody broke by giving them an agent that has a number to treat of 1 in 60."

The multinational LEADER researchers enrolled 9,340 patients into the study, assigning 4,468 patients to liraglutide, beginning at a dose of 0.6 mg once a day and then titrating the dose to 1.8 mg once a day plus standard of care for diabetes treatment. They assigned the other 4,672 patients to placebo plus standard of care. The patients were treated for a median of 3.8 years.

Mean patient age was 64, and 64% of the cohort were men. The patients had been diagnosed with diabetes for almost 13 years before entering the trial. About 355 of the patients were Europeans; another 30% were from North America. Their baseline HbA1c averaged 8.7% and mean baseline body mass index was 32.5 kg/m2; their average body weight was about 92 kg. About 18% of the patients in both arms of the trial had been diagnosed with heart failure.

Zinman reported that after 36 months, the difference in HbA1c was about 0.4 percentage points lower in the liraglutide patients versus the placebo group, a difference that was statistically significant (P<0.01). The placebo patients had lowered their HbA1c from 8.7% to about 8%; the liraglutide patients had lowered their HbA1c from 8.7% to about 7.6%.

Patients on liraglutide achieved a mean 2.3-kg reduction in body weight during the 3-year study with a similar decrease among the placebo patients, Zinman said.

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