Use of insulin or sulfonylureas as second-line treatment in adults with type 2 diabetes is associated with increased cardiovascular risk, whereas use of newer classes of glucose-lowering drugs is not, new real-world research from the United States indicates.

The findings, from a retrospective analysis of national administrative claims data, were published online published online in JAMA Network Open by Matthew J. O'Brien, MD, of the Division of General Internal Medicine and Geriatrics, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, and colleagues. 

Among more than 130,000 insured adults with type 2 diabetes who required a second glucose-lowering agent after metformin, use of insulin or sulfonylureas was associated with consistent cardiovascular harm compared with dipeptidyl peptidase 4 (DPP-4) inhibitors, which have been shown to have a neutral cardiovascular effect.

Cardiovascular Harm

On the other hand, glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and thiazolidinediones (TZDs) were not associated with cardiovascular harm compared with DPP-4 inhibitors, but they also didn't produce the significant cardiovascular benefit that has been demonstrated in randomized clinical outcome trials of these agents in patients with type 2 diabetes and established cardiovascular disease.

Such high-risk populations have typically been necessary for statistical power in US Food and Drug Administration-mandated cardiovascular outcomes trials (CVOTs), but aren't representative of the adult type 2 diabetes population as a whole, of whom just 18% have established cardiovascular disease. Moreover, CVOTs are conducted on only one drug compared with placebo.

"To date, no studies have directly compared the cardiovascular effects of all contemporary [glucose-lowering drug] options among patients starting second-line therapy By examining cardiovascular outcomes among patients initiating second-line [glucose-lowering drugs] in the real world, this study aimed to complement findings from individual drug trials and further inform [glucose-lowering drug] choices for the broad population of patients currently receiving these medications," the investigators say.

In an accompanying editorial, Alison Callahan, PhD, and Nigam H. Shah, MBBS, PhD, both of the Center for Biomedical Informatics Research, Stanford University School of Medicine, California, praise the study, noting that it "targets an area of significant clinical uncertainty with the potential to inform the treatment of millions of individuals with type 2 diabetes," and in doing so "makes an important contribution to this area."

Callahan and Shah note that the findings agree with their recent studyexamining the real-world impact of various classes of second-line glucose-lowering agents on glycemic control and complication rates, including myocardial infarction. This new study makes "a valuable contribution" by adding GLP-1 receptor agonists.