Regardless of their exact molecular structure, glucagon-like peptide 1 (GLP-1)-receptor agonists have heart and kidney benefits and reduce all-cause mortality in type-2 diabetes, a new systematic review and meta-analysis shows.

"The cardioprotective effects of human and exendin-4-basedGLP-1 receptor agonists, including reductions in the risk of hospital admission for heart failure and worsening kidney function, represent an important treatment opportunity to reduce morbidity and mortality in patients with type 2 diabetes," researchers write in The Lancet Diabetes and Endocrinology.

Dr. Naveed Sattar of the University of Glasgow, in the U.K., and his colleagues searched the literature for randomized controlled trials including more than 500 adult type-2 diabetes patients. Primary outcomes included cardiovascular death, non-fatal stroke, and non-fatal myocardial infarction, and both injectable and oral GLP-1-receptor agonists were included.

Eight studies, totaling more than 60,080 patients, met the inclusion criteria, and new data from AMPLITUDE-O was incorporated into the analysis.

Overall, GLP-1-receptor agonists reduced major adverse cardiovascular events (MACE) by 14% (hazard ratio, 0.86; P<0.0001), with no significant differences across agonist structural homology or eight other subgroups.

GLP-1-receptor agonists also cut all-cause mortality by 12% (HR, 0.88; P=0.0001), hospital admission for heart failure by 11% (HR, 0.89; P=0.013) and composite kidney outcome by 21% (HR, 0.79; P<0.0001), with no increased risk of severe hypoglycemia, pancreatic problems, or retinopathy.

Dr. Tannaz Moin of the David Geffen School of Medicine at the University of California, Los Angeles, who studies diabetes interventions, said, "GLP-1-receptor agonists have transformed our approach to diabetes care by offering new mechanisms to achieve improved blood glucose control and other benefits such as weight loss and cardiovascular mortality protection."

"This study reinforces what we already know to be among the many benefits of GLP-1-receptor agonists and provides more evidence to support their use in patients with type-2 diabetes," Dr. Moin, who was not involved in the study, told Reuters Health by email. "It is reassuring to see that the incidence of side effects, such as severe hypoglycemia, pancreatitis, and retinopathy, did not differ between GLP-1 receptor agonist treatment and placebo."

"This study has several strengths, including the number of high-quality studies included and estimates of pooled effects across several subgroups of interest," she said. "However, the authors note they did not assess for publication bias or gastrointestinal side effects."

Dr. E. Dale Abel, a professor of internal medicine at the University of Iowa Carver College of Medicine in Iowa City, told Reuters Health by email, "The data continue to support the importance of GLP-1-receptor agonists as a class of anti-diabetic agents that have strong cardioprotective qualities."

"Finding a benefit in heart failure and chronic kidney disease was unexpected, based on previous results from earlier studies," said Dr. Abel, also not involved in the study. "The results suggest that the beneficial effect in these areas is smaller than those seen in studies utilizing sodium-glucose cotransporter-2 (SGLT2) inhibitors, which were robustly observed in smaller trials."

Dr. Abel cautioned that, as a meta-analysis, "the overall results could be skewed by the results of the most recently added trials. Therefore, although highly suggestive, they do not prove that the beneficial effects described are equally applicable across all classes."

In a linked editorial, Dr. Darren K. McGuire of the University of Texas Southwestern Medical Center in Dallas, and Dr. Neha J. Pagidipati of Duke University Medical Center in Durham, North Carolina, write, "GLP1 receptor agonists remain woefully underused in contemporary clinical 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."

They recommend that "systematic efforts targeting education about, and implementation of, these efficacious agents should be a priority for clinicians, researchers, and funders alike."

Dr. Sattar did not reply to requests for comment. 

The study was not funded. All of the authors declared financial ties to drugmakers.

SOURCES: https://bit.ly/38Tb242 and https://bit.ly/3ttDSRO The Lancet Diabetes and Endocrinology, online August 20, 2021.