In patients with type 2 diabetes, glucagon-like peptide-1 (GLP-1) receptor agonists, regardless of their molecular structure, improved cardiovascular, kidney, and mortality outcomes, an updated meta-analysis found.
Researchers conducted a systematic review and meta-analysis of randomized placebo-controlled trials that tested either injectable or oral GLP-1 receptor agonists in patients with type 2 diabetes and reported major adverse cardiovascular events (MACE) up to June 9, 2021. Eligible trials included more than 500 patients and had a primary outcome that included cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. The review also looked at two renal outcomes: worsening kidney function, defined as either doubling of serum creatinine or at least 40% decline in estimated glomerular filtration rate (eGFR), and a composite of macroalbuminuria, doubled serum creatinine, at least 40% decline in eGFR, kidney replacement therapy, or death due to kidney disease. Results were published online on Aug. 20 by The Lancet Diabetes & Endocrinology.
A total of eight trials comprising 60,080 patients were included. Overall, GLP-1 receptor agonists reduced MACE by 14% (hazard ratio [HR], 0.86 [95% CI, 0.80 to 0.93]; P<0.0001), with no significant heterogeneity across GLP-1 receptor agonist structural homology or other examined subgroups. GLP-1 receptor agonists reduced all-cause mortality by 12% (HR, 0.88 [95% CI, 0.82 to 0.94]; P=0.0001), hospital admission for heart failure by 11% (HR, 0.89 [95% CI, 0.82 to 0.98]; P=0.013), and the composite kidney outcome by 21% (HR, 0.79 [95% CI, 0.73 to 0.87]; P<0.0001), with no increase in risk of severe hypoglycemia, retinopathy, or pancreatic adverse effects. In sensitivity analyses that removed the only trial restricted to patients with acute coronary syndrome, all benefits marginally increased, including the outcome of worsening of kidney function (HR, 0.82 [95% CI, 0.69 to 0.98]; P=0.030).
Among other limitations, the study couldn't assess how GLP-1 receptor agonists work with sodium-glucose cotransporter-2 inhibitors due to insufficient patient numbers. The researchers added that they did not assess gastrointestinal side effects, which are “universally increased with the use of GLP-1 receptor agonists, especially when starting such therapies.”
An accompanying comment noted that the data show a broad array of benefits associated with GLP-1 receptor agonists, but added an important caveat to the finding of reduced heart failure hospitalizations: The result was driven by two trials that evaluated GLP-1 receptor agonists that have not been approved for clinical use. The commenters also noted that the drug class remains underused in practice. “Part of this underuse is undoubtedly due to the barrier of cost because these medications are exorbitantly priced and inaccessible for a large proportion of patients with type 2 diabetes,” the authors wrote. “In addition, there is the challenge of busy practitioners keeping up with the data and clinical inertia, both of which can be addressed with systematic educational programmes and processes. Such systematic efforts targeting education about, and implementation of, these efficacious agents should be a priority for clinicians, researchers, and funders alike.”