Round-up of the GLP-1 receptor agonist CV outcome trials
Five cardiovascular (CV) outcome trials for glucagon-like peptide (GLP)-1 receptor agonists in patients with type 2 diabetes have so far reported their primary findings, with two still to report.
As stipulated by the regulatory authorities, patients in these trials were randomly assigned to receive the GLP-1 receptor agonists in question versus placebo, with other medications added as needed to control blood glucose, and were followed up for a sufficient duration to demonstrate noninferiority of the active treatment for CV outcomes.
Here we provide a brief overview of the results published so far and list the trials still in progress. Please refer to our feature article for a more in-depth discussion with John Petrie from the University of Glasgow, UK.
|Medication: lixisenatide, daily injection||N=6068; 100% with recent (≤180 days) acute coronary syndromes|
ELIXA was the first of these trials to publish, in 2015 in The New England Journal of Medicine. The statistical design allowed for proof of both noninferiority and, if possible, superiority, based on a 4-point major adverse cardiovascular event (MACE) endpoint of death from CV disease (CVD), nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina.
In the event, 13.4% and 13.2% of patients from the lixisenatide and placebo groups, respectively, met the primary outcome, giving a decidedly neutral hazard ratio of 1.02, with individual and secondary endpoints giving similar results.
|Medication: liraglutide, daily injection||N=9340; 81.3% with baseline CVD or chronic kidney disease stage 3+|
The LEADER trial was conducted in high-risk patients, but most had stable CVD or risk factors rather than unstable disease, and contrary to ELIXA it reported a significant cardioprotective effect for liraglutide. Patients taking the medication had a significant 13% reduction in the risk for a 3-point MACE (CV death, myocardial infarction, or stroke) endpoint, at a rate of 13.0% versus 14.9% in the placebo group. The effects on individual and secondary endpoints were in line with the primary outcome analysis.
Related news story: Liraglutide cardioprotective in high-risk Type 2 diabetes patients
|Medication: semaglutide, weekly injection|
N=3297; 83% with baseline CVD or chronic kidney disease stage 3+
Following on from LEADER, SUSTAIN-6 also reported positive results. Although not designed to test superiority, the trial nevertheless showed a significant 26% reduction in the risk for the 3-point MACE endpoint among patients taking semaglutide versus the control group, with most secondary CV endpoints following a similar pattern.
Related news story: Favorable cardiovascular safety profile for semaglutide
|Medication: exenatide, weekly injection||N=14,752; approx 76% with baseline CVD or chronic kidney disease stage 3+|
In May 2017, exenatide’s manufacturer released a nondescript press statement noting that the medication had met its noninferiority endpoint in EXSCEL, but was not statistically superior. But the full results, reported later in the year, revealed more of a near miss. In all, 11.4% versus 12.2% of patients taking exenatide and placebo, respectively, met the 3-point MACE primary endpoint. This gave a hazard ratio of 0.91, with a 95% confidence interval of 0.83 to 1.00 and a p value of 0.06. The individual endpoints followed the same pattern, with the reduction in death from any cause being potentially statistically significant, and in most prespecified subgroup analyses the hazard ratio was less than 1.0.
Related news story: EXSCEL: Near miss for exenatide cardioprotection
|Medication: albiglutide, weekly injection||N=9463; all with established coronary, cerebrovascular, or peripheral artery disease|
In 2017, albiglutide's manufacturer elected to cease investment in the medication for commercial reasons, but nonetheless supported the HARMONY Outcomes trial to completion.
And the results, reported in The Lancet in October 2018, were favorable. Over a median follow-up of 1.6 years, 7% of patients assigned to albiglutide versus 9% of those given placebo met the 3-point MACE primary endpoint. This equated to event rates of 4.57 versus 5.87 per 100 person–years and a significant 22% risk reduction for patients in the albiglutide group.
Related news story: Albiglutide reduces cardiovascular risk in patients with type 2 diabetes
Still to report
Two more relevant trials are yet to report. One is REWIND, testing the weekly injectable dulaglutide, but notable because only a third of participants had established CVD at baseline. The topline findings, press-released in November 2018, indicate that dulaglutide treatment significantly reduced rates of the 3-point MACE primary outcome.
The final trial is PIONEER 6, which is testing a daily oral preparation of semaglutide. The press-released topline results point to a strong trend toward cardioprotection, driven by a significant reduction in the risk for cardiovascular death.
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