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GLP-1 receptor agonists reduce CV events across large outcomes trials
A meta-analysis of seven large cardiovascular outcomes trials suggests that treatment with GLP-1 receptor agonists reduces major adverse cardiovascular events by 12%, all-cause mortality by 12% and hospitalization for heart failure by 9% among adults with type 2 diabetes when compared with placebo, according to findings published in The Lancet Diabetes & Endocrinology.
John J. V. McMurray, MD, professor of cardiology at the Institute of Cardiovascular and Medical Sciences at University of Glasgow in Scotland, and colleagues analyzed data from seven CV outcomes trials reporting major adverse CV events among 56,004 participants with type 2 diabetes with and without a history of CVD: ELIXA (lixisenatide), LEADER (liraglutide), SUSTAIN-6 (semaglutide), EXSCEL (exenatide), Harmony Outcomes (albiglutide), REWIND (dulaglutide), and PIONEER 6 (oral semaglutide). Researchers used a random-effects model to estimate overall HRs for major adverse CV events and their components, death of any cause, hospital admission for heart failure, kidney outcomes, and key safety outcomes (severe hypoglycemia, pancreatitis and pancreatic cancer). Researchers also examined major adverse CV events in several subgroups based on patient characteristics (history of CVD, BMI, age, baseline HbA1c and baseline estimated glomerular filtration rate), trial duration, treatment dosing interval and structural homology.
Reduction in CV, renal events
Overall, GLP-1 receptor agonist therapy reduced major adverse CV events by 12% (HR = 0.88; 95% CI, 0.82-0.94). No statistically significant heterogeneity existed across the subgroups examined.
HRs were 0.88 (95% CI, 0.81-0.96) for CV death, 0.84 (95% CI, 0.76-0.93) for fatal or nonfatal stroke and 0.91 (95% CI, 0.84-1) for fatal or non-fatal myocardial infarction.
GLP-1 receptor agonist therapy reduced all-cause mortality by 12% (HR = 0.88; 95% CI, , 0.83–0.95), hospital admission for heart failure by 9% (HR = 0.91; 95% CI, 0.83-0.99), and a broad composite kidney outcome — defined as development of new-onset macroalbuminuria, decline in eGFR, progression to end-stage kidney disease or death attributable to kidney causes — by 17% (HR = 0.83; 95% CI, 0.78-0.89), mainly due to a reduction in urinary albumin excretion. There was no increase in risk for severe hypoglycemia, pancreatitis or pancreatic cancer.
“Overall, GLP-1 receptor agonists are clearly cardioprotective drugs,” the researchers wrote. “The time course of their effects, apparent in the individual trials, and the types of cardiovascular events prevented, suggest that GLP-1 receptor agonists have mainly an anti-atherothrombotic effect. This profile is distinct from that of the SGLT2 inhibitors, which show an effect on cardiovascular outcomes much more rapidly, with a more pronounced effect on heart failure, raising the possibility of therapeutic synergy from the combination of these two classes of antidiabetes drugs.”
‘Unexpected’ findings
In a commentary accompanying the study, Eberhard Standl, MD, PhD, chairman and professor of medicine at the Munich Diabetes Research Group e.V. at Helmholtz Center in Neuherberg, Germany, wrote that the inclusion of data from seven large-scale trials allowed Kristensen and colleagues to assess additional outcomes and conduct several subgroup analyses for major adverse CV events.
“Unexpectedly, a reduction of hospital admission for heart failure with GLP-1 receptor agonist treatment was shown for the first time,” Standl wrote. “Although this was a pooled analysis of a secondary outcome and the effect was of borderline statistical significance and was much smaller than that seen with SGLT2 inhibitors, this finding contrasts remarkably with early concerns regarding GLP-1 receptor agonist-associated heart failure problems.”
Standl noted that, in subgroup analyses of the primary major adverse CV event outcome, the investigators reported a consistent benefit across patients with established CVD and those in primary prevention groups, based on a nonsignificant P value for interaction. “However, the HR for the primary prevention group of 0.95 (95% CI, 0.83-1.08) does not seem particularly convincing, and this result seems to be largely driven by data from REWIND (which provided about 50% of the primary prevention patients in the meta-analysis), given that previous trials with primary prevention populations have had HRs for that subgroup of 1.2, 1 and 0.99 — ie, no signal of benefit whatsoever,” Standl wrote. “As such, this important issue needs rigorous further exploration before treatment approaches can be revised.” – by Regina Schaffer
Disclosures: McMurray reports payment to his institution from AbbVie, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, DalCor, GlaxoSmithKline, Merck, Novartis, Resverlogix and Theracos for his participation in clinical trials, and from Alnylam, AstraZeneca, Cardurion, Novartis and Pfizer for consultant/advisory board membership or lectures. Please see the study for all other authors’ relevant financial disclosures. Standl reports lecturing honoraria and consulting fees from AstraZeneca, Bayer, Berlin-Chemie, Boehringer Ingelheim, Merck Serono, Merck Sharp & Dohme, Novartis, Novo Nordisk and Sanofi.