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Harmony Outcomes adds to CV benefit profile of GLP-1 agonists in T2D

Roshini Claire Anthony
30 Oct 2018

Patients with type 2 diabetes (T2D) and cardiovascular disease (CVD) had fewer major CV events when given the GLP-1* receptor agonist albiglutide compared with placebo, adding to the CV benefit profile of GLP-1 receptor agonists, according to results of the Harmony Outcomes** trial presented at EASD 2018.

“In patients with T2D and established CVD receiving standard care, the addition of albiglutide led to a relative reduction of 22 percent in the risk of CV death, [myocardial infarction (MI)], or stroke compared with the addition of placebo,” said study investigator Professor John McMurray from the British Heart Foundation Glasgow in Glasgow, UK.

The multinational (610 sites in 28 countries), double-blind trial involved 9,463 patients (mean age 64.1 years, 31 percent female, mean HbA1c 8.7 percent) with T2D and CVD who were randomized to receive once-weekly doses of either subcutaneous albiglutide (30–50 mg; n=4,731) or placebo (n=4,732) plus standard of care. Patients were followed up for a median 1.6 years. The use of other glucose-lowering medications including SGLT-2*** and DPP-4# inhibitors was permitted.

Fewer patients who received albiglutide experienced the composite primary outcome of CV death, non-fatal MI, or non-fatal stroke compared with those who received placebo (7 percent vs 9 percent, incidence rate, 4.6 vs 5.9 per 100 person-years, hazard ratio [HR], 0.78, 95 percent confidence interval [CI], 0.68–0.90 with upper limit of 95 percent CI <1.30 and <1.00, respectively, signalling noninferiority and superiority of albiglutide to placebo; p<0.0001 for noninferiority and p=0.0006 for superiority). [EASD 2018, oral presentation S04.5; Lancet 2018;doi:10.1016/S0140-6736(18)32261-X]

Examination of individual components of the primary outcome showed no significant differences between albiglutide and placebo recipients except for fatal or non-fatal MI which occurred less often in albiglutide recipients (HR, 0.75; p=0.003). The addition of urgent coronary revascularization for unstable angina to the composite primary outcome still demonstrated the noninferiority of albiglutide to placebo (HR, 0.78; p=0.0005).

The incidence of severe adverse events (AEs) was comparable between patients given albiglutide and placebo, specifically acute pancreatitis (n=10 vs 7), pancreatic cancer (n=6 vs 5), and medullary thyroid carcinoma (n=0 in each group). Severe hypoglycaemia occurred less frequently in albiglutide compared with placebo recipients (n=31 vs 55). AE-related discontinuations occurred in nine and six percent of albiglutide and placebo recipients, respectively. The need for new insulin treatment was also less frequent among those assigned to albiglutide compared with placebo (6 percent vs 13 percent; p<0.0001).

 

Albiglutide demonstrates GLP-1 receptor agonist class effect

“The Harmony Outcomes results strengthen the case for the use of GLP-1 inhibitors, as a class, in patients with atherosclerotic CVD,” said Dr Marion Mafham and Associate Professor David Preiss from the Nuffield Department of Population Health, Oxford, UK, in a commentary. [Lancet 2018;doi:10.1016/S0140-6736(18)32348-1]

“We found compelling evidence of [major adverse CV event (MACE)] benefit despite only modest metabolic improvements,” said study author Professor Lawrence Leiter from St Michael’s Hospital, Toronto, Ontario, Canada. “[O]ur findings highlight the fact that the CV benefits of this class of medications likely are above and beyond any metabolic effects of these drugs.” [EASD 2018, oral presentation S04.7]

“Harmony Outcomes adds further support that evidence-based GLP-1 receptor agonists should be part of a comprehensive strategy to reduce the risk of CV events in T2D, as recommended in recent cardiology and diabetes guidelines,” he added. In accordance with the findings, the study sponsor and manufacturer of albiglutide announced that they would “seek a way to make albiglutide available to patients through another company”, said Leiter.

Mafham and Preiss pointed out that the short-term follow-up times may have been insufficient to obtain conclusive results. As the mechanism behind the reduction of atherosclerotic CV events with albiglutide and other GLP-1 receptor agonists is undetermined, they also highlighted the importance of studies assessing the impact of this drug class in individuals with CVD but not T2D as the CV benefits may not necessarily be glycaemia-mediated.

 

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