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
Related expert interview: GLP-1 receptor agonists: Cardiovascular trials and triumphs
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.
The manufacturer stated its intention "to divest this medicine to a company with the right expertise and resources to realise its full potential for patients."
Related news story: Albiglutide reduces cardiovascular risk in patients with type 2 diabetes
Medication: dulaglutide, weekly injection
N=9901; 31.5% with established CVD
The REWIND trial, reported in June 2019 in The Lancet, is the only trial to have recruited a majority of people who, although at high risk, did not have established CVD.
The investigators found a significant 12% reduction in risk for the 3-point MACE outcome, and reported that a risk reduction was evident regardless of whether participants had established CVD.
The trial findings therefore suggest that GLP-1 receptor agonists may be cardioprotective even in patients who have not yet had a clinical event.
Related news story: Dulaglutide cardioprotective in relatively low-risk REWIND population
Expert commentary: WATCH: John Wilding discusses REWIND
Expert commentary: WATCH: A nurse educator’s view of the REWIND trial
Medication: semaglutide, daily oral
N=3183; 84.7% with established CVD or renal disease
The PIONEER series of clinical trials were launched to test the novel oral version of semaglutide, with PIONEER 6, published in The New England Journal of Medicine, testing its cardiovascular safety.
The trial demonstrated statistically noninferior cardiovascular safety to placebo, but the event-driven trial had limited power to demonstrate superiority. There was, however, a general trend toward cardioprotection, with a nonsignificant hazard ratio of 0.79 and a confidence interval of 0.57–1.11, seemingly driven by a reduced risk for CVD mortality.
Related news story: Oral semaglutide falls just short of cardioprotection in event-driven PIONEER 6
Expert commentary: WATCH: Lead researcher Mansoor Husain talks about the trial
Medication: efpeglenatide, weekly injection
N=4076; with established CVD (89.6%) or renal (31.6%) disease
In the AMPLITUDE-O trial, reported in The New England Journal of Medicine, efpeglenatide achieved statistical superiority to placebo despite the sponsor pulling funding before the intended number of primary outcome events had accrued.
There were 314 events, rather than the intended 330, but rates of 7.0% versus 9.2% with efpeglenatide (4 or 6 mg) versus placebo equated to a significant 27% reduction in risk for the 3-point MACE primary outcome.
Efpeglenatide treatment also produced a significant reduction in risk for the secondary endpoint of a composite renal outcome.
Related news story: AMPLITUDE-O: Efpeglenatide offers cardiorenal protection in type 2 diabetes
Still to report
Following on from PIONEER 6, the much larger SOUL trial is powered to test whether oral semaglutide is cardioprotective in an estimated 9642 participants. It is not expected to complete until mid 2024.
In addition, the SELECT trial is recruiting people with overweight or obesity who have established CVD but do not have diabetes, to assess the CV safety of semaglutide 2.4 mg/week.
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