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People with type 2 diabetes reaped multiple benefits when GLP-1 receptor agonists (RAs) were incorporated into their treatment regimens, researchers reported.

In a systematic review and meta-analysis of seven trials reporting major adverse cardiovascular events (MACE), use of GLP-1 RAs resulted in a 12% overall reduction in MACE (HR 0.88, 95% CI 0.82–0.94, P<0.0001), Søren Kristensen, MD, of the University of Glasgow in Scotland, and colleagues wrote in .

MACE reduction was mainly driven by a significant drop in fatal or non-fatal stroke (HR 0.84, 95% CI 0.76-0.93), although risks for cardiovascular death (HR 0.88, 95% CI 0.81-0.96) and fatal or non-fatal myocardial infarction (HR 0.91, 95% CI 0.84-1.00) were also significantly reduced.

The meta-analysis included outcomes on a total of 56,004 adults with type 2 diabetes who participated in one of the following trials:

• ELIXA: lixisenatide (Adlyxin)

• LEADER: liraglutide (Victoza)

• SUSTAIN-6: injectable semaglutide (Ozempic)

• EXSCEL: exenatide (Bydureon, Byetta)

• Harmony Outcomes: albiglutide (Tanzeum)

• REWIND: dulaglutide (Trulicity)

• PIONEER 6: oral semaglutide (investigational)

Back in 2008, the FDA issued guidance for industry requiring a randomized MACE cardiovascular outcomes trial for new type 2 diabetes treatments.

"Although the primary objective of demonstrating cardiovascular safety ... by assessing a composite outcome of MACE ... has been met by all of about 20 such cardiovascular outcome trials assessing five different classes of diabetes medications reported since 2012, cardiovascular benefit has been only shown for drugs from the GLP-1 receptor agonist and sodium-glucose co-transporter-2 (SGLT2) inhibitor classes," explained Eberhard Standl, MD, PhD, of the Munich Diabetes Research Group e.V. at Helmholtz Center in Germany, writing in an .

Delving deeper into MACE outcomes, Kristensen and co-authors conducted subgroup analyses, finding no statistical heterogeneity -- marked by a P value of 0.22 for interaction -- for patients who already had established cardiovascular disease versus primary prevention patients.

However, Standl wrote, "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 1.20, 1.00, and 0.99 -- i.e., no signal of benefit whatsoever."

Looking beyond a benefit in MACE reduction, Kristensen's group also found that GLP-1 RAs were associated with a 12% overall reduction in all-cause mortality (HR 0.88, 95% CI 0.83-0.95, P=0.001). Additionally, there was also a 9% drop in hospital admission for heart failure (HR 0.91, 95% CI 0.83-0.99, P=0.028), which Standl noted was both "unexpected" and "shown for the first time."

"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 SGLT-2 inhibitors (0.69, [number needed to treat] about 100), this finding contrasts remarkably with early concerns regarding GLP-1 receptor agonist associated heart failure problems," he explained.

When assessing broad composite kidney outcomes, which excluded the Harmony Outcomes (albiglutide) and PIONEER 6 (oral semaglutide) trials, there was a 17% reduction in adverse kidney outcomes including macroalbuminuria with GLP-1 RAs (HR 0.83, 95% CI 0.78-0.89, P<0.0001). A drop in urinary albumin excretion chiefly drove this risk reduction, while the benefit on estimated glomerular filtration rate decline was less pronounced than has been documented with SGLT-2 inhibitors, Standl said.

Overall, the meta-analysis concluded that GLP-1 RAs were associated with few adverse events, without any increased risk in severe hypoglycemia, thyroid cancer, pancreatitis or pancreatic cancer, or eye problems.

Standl said that despite how the study "nicely synthesize[d]" data from all the major GLP-1 RA trials, questions still linger about this class of antidiabetic agents, particularly when used for primary cardiovascular prevention.