Cardiovascular Outcomes in Patients with Type 2 Diabetes Who Added Either GLP1 Receptor Agonists or DPP4 Inhibitors to SGLT2 Inhibitor Therapy

Background: Most patients with type 2 diabetes require combination glucose-lowering therapy; however, the effectiveness or safety of combination therapies are rarely assessed in either randomized trials or observational studies. Emerging data suggest that the combination of sodium-glucose co-transporter 2 inhibitors (SGLT2i) and a glucagon-like peptide-1 receptor agonists (GLP-1RA) may yield complementary cardiovascular benefit.

Objectives: To compare cardiovascular benefits of adding GLP-1RA versus dipeptidyl peptidase 4 inhibitors (DPP-4i) in patients on SGLT2i therapy.

Methods: Using 3 US claims datasets (2013-2019), we conducted a cohort study of patients with type 2 diabetes who initiated either GLP-1RA or DPP-4i (index drug) while on SGLT2i therapy. Patients were 1:1 matched on their propensity score (PS) within each dataset and followed from the day after initiation of index drug (GLP-1RA or DPP-4i) for as long as they were exposed to both SGLT2i and index exposure. Secondary analysis included an intention-to-treat (ITT) approach where patients were followed for 365 days regardless of changes in therapy. Primary outcome was a composite of myocardial infarction (MI) or stroke. Secondary outcomes included MI, stroke, all-cause mortality, the composite of MI, stroke or all-cause mortality, and hospitalization for heart failure (HHF). Adjusted hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional hazard model in each dataset and in the pooled data, stratifying on a dataset.

Results: The PS-matched cohort comprised 41,586 GLP-1RA initiators and 41,586 DPP4i initiator (mean age 60 years, 55% men). Over the mean follow-up of 169 days, the primary outcome occurred in 215 GLP-1RA initiators (incidence rate [IR] 11.3 per 1,000 person-years) and in 258 DPP4i initiators (IR 13.1 per 1,000 person-years) with the HR of 0.87 (95% CI 0.72-1.04) for GLP-1RA as compared with DPP-4i. The results were similar for the secondary outcomes; however, patients initiating GLP-1RA while on SGLT2i had lower rates of HHF (HR 0.57; 95% CI 0.41-0.80). The ITT analysis yielded more attenuated association for HHF (HR 0.78; 95% CI 0.63-0.96), but stronger association for the primary outcome (HR 0.81; 95% CI 0.70-0.92).

Conclusions: In this large cohort study of US patients with type 2 diabetes already treated with SGLT2i therapy, the addition of GLP1RA — compared to DPP4i — was associated with reduced risk of HHF in primary, as-treated analysis, and reduced risk of MI/stroke in ITT analysis. The follow-up was short, however, and the risk of residual confounding cannot be ruled out.