Cardiovascular event rates similar among newer second-line medications for type 2 diabetes

The comparison of dipeptidyl peptidase-4 inhibitors with other drug classes did find higher rates of major adverse cardiovascular events with basal insulin, sulfonylureas, and meglitinides than with the newer drugs.


Starting glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, or thiazolidinediones was not associated with an increased risk of cardiovascular events compared to starting dipeptidyl peptidase-4 (DPP-4) inhibitors, a recent study found.

Researchers used U.S. administrative claims data from 2011 through 2015 to conduct a retrospective cohort study of 132,737 insured adults with type 2 diabetes. Sixty-three percent were white, 45% were women, and 58% were 45 to 64 years of age. Participants started therapy with a second-line antidiabetic medication (e.g., DPP-4 inhibitors, GLP-1 receptor agonists, SGLT-2 inhibitors, thiazolidinediones, basal insulin, sulfonylureas, or meglitinides) after taking either metformin alone or no prior antidiabetic medication.

Using DPP-4 inhibitors as the comparison group, the researchers assessed time to first cardiovascular event (a composite outcome based on hospitalization for congestive heart failure, stroke, ischemic heart disease, or peripheral artery disease) after starting the second-line drug. They censored patients after the first cardiovascular event, discontinuation of insurance coverage, transition from ICD-9 to end of ICD-9 coding, or two years of follow-up. Results were published online on Dec. 21, 2018, by JAMA Network Open.

Overall, there were 3,480 incident cardiovascular events during 169,384 person-years of follow-up (mean, 1.3 years). After adjustment for patient, prescriber, and health plan characteristics, the risk of composite cardiovascular events after starting GLP-1 receptor agonists was lower than that of DPP-4 inhibitors (hazard ratio [HR], 0.78; 95% CI, 0.63 to 0.96), but this result was not significant in all sensitivity analyses. Cardiovascular event rates after starting SGLT-2 inhibitors (HR, 0.81; 95% CI, 0.57 to 1.53) and thiazolidinediones (HR, 0.92; 95% CI, 0.76 to 1.11) were not significantly different from DPP-4 inhibitors. For patients starting sulfonylureas or meglitinides (which were grouped together) and basal insulin, the comparative risk of cardiovascular events was higher than for those taking DPP-4 inhibitors (HRs, 1.36 [95% CI, 1.23 to 1.49] and 2.03 [95% CI, 1.81 to 2.27], respectively).

The study authors noted limitations, such as a lack of information on diabetes duration and the possibility of misclassification within the administrative claims data. Given the results, “[C]linicians may consider prescribing GLP-1 receptor agonists, DPP-4 inhibitors, or SGLT-2 inhibitors more routinely after metformin rather than sulfonylureas [or meglitinides] or basal insulin,” they concluded.

Previous research in this area has been inconsistent, and recommendations vary for second-line treatment of type 2 diabetes, so this study “makes an important contribution,” according to an accompanying editorial. “The study … targets an area of significant clinical uncertainty with the potential to inform the treatment of millions of individuals with type 2 diabetes,” the editorialists wrote.