According to study results published in JAMA Network Open, increased cardiovascular (CV) risk among patients with type 2 diabetes (T2D) starting second-line therapy was associated with sulfonylureas and basal insulin use, while newer antidiabetic medications had a neutral effect on CV outcomes.

The investigators of this retrospective cohort study sought to compare the effectiveness of contemporary antidiabetic medications on major CV outcomes in patients with T2D starting second-line therapy.

The study cohort included 132,737 insured adults with T2D enrolled in commercial or Medicare Advantage health insurance plans. Participants were initiated on second-line antidiabetic medications after taking metformin as a monotherapy or having no prior treatment with antidiabetic medications. 

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Over a 2-year period, the investigators compared the efficacy of 6 classes of antidiabetic medications used as second-line therapy: dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, sodium-glucose cotransporter 2 (SGLT-2) inhibitors, thiazolidinediones, basil insulin, and sulfonylureas. DPP-4 inhibitors served as the comparison class in this study, as previous trials have indicated its neutral effect on CV events. Time to first CV event after initiating second-line antidiabetic medication was the primary study outcome; CV events included hospitalizations for congestive heart failure, stroke, ischemic heart disease, or peripheral artery disease.

In total, 3480 inpatient CV events were reported during the course of the study. After adjusting for variables, risk for composite CV events after starting second-line therapy with GLP-1 receptor agonists was lower than with DPP-4 inhibitors (hazard ratio [HR], 0.78; 95% CI, 0.63-0.96). However, this comparison was not considered significant in sensitivity analyses accounting for adherence, blood glucose levels, and comorbidity. CV risk associated with starting DPP-4 inhibitors was statistically similar after treatment with SGLT-2 inhibitors (HR, 0.81; 95% CI, 0.57-1.53) and thiazolidinediones (HR, 0.92; 95% CI, 0.76-1.11). Compared with second-line treatment with DPP-4 inhibitors, risk for CV events was 36% higher in patients after starting sulfonylureas (HR, 1.36; 95% CI, 1.23-1.49) and doubled in patients after starting basal insulin (HR, 2.03; 95% CI, 1.81-2.27); these associations remained robust in sensitivity analyses.

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One limitation to the study was the cohort consisting only of patients with a known burden of CV disease taking multiple antidiabetic medications, preventing the generalizability of the results to a broader population with diabetes. Patients were also required to fill the index antidiabetic medication at least twice; discontinuation after the first fill may have been related to CV outcomes, potentially underestimating the extent of CV harm reported in the study. In addition, no data on body weight or diabetes duration were available, which may have impacted CV risk.

Patients with T2D who initiated second-line antidiabetic medication therapy demonstrated similar CV risk after starting GLP-1 receptor agonists, SGLT-2 inhibitors, and DPP-4 inhibitors, which was below the threshold of harm. “Clinicians may consider prescribing GLP-1 receptor agonists, SGLT-2 inhibitors, or DPP-4 inhibitors more routinely after metformin rather than sulfonylureas or basal insulin,” concluded the researchers.

This study was sponsored by a grant to Northwestern University from United Healthcare Services.

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O’Brien MJ, Karam SL, Wallia A, et al. Association of second-line antidiabetic medications with cardiovascular events among insured adults with type 2 diabetes. JAMA Netw Open. 2018;1(8):e186125.