Human, exendin-based GLP-1 receptor agonists similarly reduce CV, renal risk in diabetes
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A pooled study assessing trials of eight GLP-1 receptor agonists showed all reduce risk for a combined endpoint of major adverse cardiovascular events, regardless of structural homology to human GLP-1, as well as individual CV components.
In a systematic review and meta-analysis of eight large-scale CV outcomes trials — pooling data for lixisenatide (Adlyxin, Sanofi), liraglutide (Victoza, Novo Nordisk), injectable semaglutide (Ozempic, Novo Nordisk), exenatide (Byetta, AstraZeneca), albiglutide (Tanzeum, GlaxoSmithKline; not available for commercial use in U.S.), dulaglutide (Trulicity, Eli Lilly), oral semaglutide (Rybelsus, Novo Nordisk) and efpeglenatide (Sanofi) — researchers also found that human and exendin-based GLP-1 receptor agonists reduce risk for all-cause mortality, hospitalization for heart failure, and a composite kidney outcome of development of new-onset macroalbuminuria, decline in estimated glomerular filtration rate or increase in creatinine, renal replacement therapy or renal death.
“The addition of AMPLITUDE-O data refined evidence for cardiovascular benefits, in particular showing reduction in hospital admission for heart failure, and suggested exendin-4-based compounds lower risks as well as human-based GLP-1 receptor agonists,” Naveed Sattar, MD, PhD, professor of metabolic medicine at the University of Glasgow in the U.K., and colleagues wrote. “Furthermore, when we repeated the meta-analysis excluding ELIXA, the trial done with a short-acting GLP-1 receptor agonist in patients with acute coronary syndrome, the outcome of worsening of kidney function, based predominantly on change in eGFR, was also improved.”
Sattar and colleagues analyzed data from eight randomized, placebo-controlled trials with 60,080 participants testing injectable or oral GLP-1 receptor agonists in adults with type 2 diabetes, including the recently presented AMPLITUDE-O. Researchers used a random-effects model to estimate overall HRs for major adverse CV events and its individual components; all-cause mortality; hospitalization for heart failure; a composite renal outcome of development of macroalbuminuria, doubling of serum creatinine, or at least 40% decline in eGFR, renal replacement therapy or death due to kidney disease; and worsening of kidney function and ORs for key safety outcomes.
Researchers also examined major adverse CV events in patient subgroups on the basis of major adverse CV event rates in the placebo group, the presence or absence of CVD, HbA1c level, trial duration, treatment dosing interval, structural homology to human GLP-1 or exendin-4, BMI, age and eGFR.
Overall, GLP-1 receptor agonists reduced major adverse CV events by 14% (HR = 0.86; 95% CI, 0.8-0.93), with no significant heterogeneity across GLP-1 receptor agonist structural homology or eight other examined subgroups.
GLP-1 receptor agonists reduced all-cause mortality by 12% (HR = 0.88; 95% CI, 0.82-0.94), heart failure hospitalization by 11% (HR = 0.89; 95% CI, 0.82-0.98) and the composite kidney outcome by 21% (HR = 0.79; 95% CI, 0.73-0.87), with no increase in risk for severe hypoglycemia, retinopathy or pancreatic adverse effects.
In sensitivity analyses removing the only trial restricted to patients with an acute coronary syndrome (ELIXA), all benefits marginally increased, including the outcome of worsening of kidney function, based on eGFR change (HR = 0.82; 95% CI, 0.69-0.98).
“The results further reinforce the evidence that GLP-1 receptor agonists reduce major adverse CV events and each of its individual components. Importantly, the benefit of GLP-1 receptor agonists injected weekly was also shown to be the same as that of agents injected daily,” the researchers wrote. “Second, the data from AMPLITUDE-O improved the certainty about the effect of GLP-1 receptor agonists on hospital admission for heart failure, with the updated meta-analysis showing an 11% reduction. Third, these new results show convincingly that major adverse CV events benefits are independent of the structural basis of the GLP-1 receptor analogue, assuaging concerns that exendin-4-based agonists are less effective than human GLP-1-based molecules.”
Perspective
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Daniel Einhorn, MD, FACE, FACP
This paper is an excellent example how a meta-analysis can be enhanced as new data (AMPLITUDE-O) is added, and as one or more studies with anomalous populations (ELIXA) are excluded in order to enable greater understanding of the findings and generalizability for guideline development.
We can now more confidently conclude from the controlled trial data that human and exendin-based GLP-1 receptor agonists are equivalent regarding all-cause mortality, major CV outcome events, hospitalization for heart failure and adverse kidney outcomes. These add to the weight of evidence establishing GLP-1 receptor agonists as first-line in the treatment paradigm for patients with type 2 diabetes. This is also a model for building on meta-analyses already published.
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