Comparative Effectiveness of Second-line Antihyperglycemic Agents for Cardiovascular Outcomes: A Large-scale, Multinational, Federated Analysis of the LEGEND-T2DM Study

Abstract

Background: SGLT2 inhibitors (SGLT2is) and GLP-1 receptor agonists (GLP1-RAs) reduce major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM). However, their effectiveness relative to each other and other second-line antihyperglycemic agents is unknown, without any major ongoing head-to-head trials.

Methods: Across the LEGEND-T2DM network, we included ten federated international data sources, spanning 1992-2021. We identified 1,492,855 patients with T2DM and established cardiovascular disease (CVD) on metformin monotherapy who initiated one of four second-line agents (SGLT2is, GLP1-RAs, dipeptidyl peptidase 4 inhibitor [DPP4is], sulfonylureas [SUs]). We used large-scale propensity score models to conduct an active comparator, target trial emulation for pairwise comparisons. After evaluating empirical equipoise and population generalizability, we fit on-treatment Cox proportional hazard models for 3-point MACE (myocardial infarction, stroke, death) and 4-point MACE (3-point MACE + heart failure hospitalization) risk, and combined hazard ratio (HR) estimates in a random-effects meta-analysis.

Findings: Across cohorts, 16·4%, 8·3%, 27·7%, and 47·6% of individuals with T2DM initiated SGLT2is, GLP1-RAs, DPP4is, and SUs, respectively. Over 5·2 million patient-years of follow-up and 489 million patient-days of time at-risk, there were 25,982 3-point MACE and 41,447 4-point MACE events. SGLT2is and GLP1-RAs were associated with a lower risk for 3-point MACE compared with DPP4is (HR 0·89 [95% CI, 0·79-1·00] and 0·83 [0·70-0·98]), and SUs (HR 0·76 [0·65-0·89] and 0·71 [0·59-0·86]). DPP4is were associated with a lower 3-point MACE risk versus SUs (HR 0·87 [0·79-0·95]). The pattern was consistent for 4-point MACE for the comparisons above. There were no significant differences between SGLT2is and GLP1-RAs for 3-point or 4-point MACE (HR 1·06 [0·96-1·17] and 1·05 [0·97-1·13]).

Interpretation: In patients with T2DM and established CVD, we found comparable cardiovascular risk reduction with SGLT2is and GLP1-RAs, with both agents more effective than DPP4is, which in turn were more effective than SUs. These findings suggest that the use of GLP1-RAs and SGLT2is should be prioritized as second-line agents in those with established CVD.

Funding: National Institutes of Health, United States Department of Veterans Affairs.

Keywords: Cardiovascular Diseases; Comparative Effectiveness Research; Diabetes Mellitus; Glucagon-Like Peptide-1 Receptor Agonists; Hypoglycemic Agents; Sodium-Glucose Transporter 2 Inhibitors; Type 2.

Figure 1:. Study Design and Analytical Methodology to Evaluate the Comparative Effectiveness of SGLT2is, GLP1-RAs, DPP4is, and SUs for Cardiovascular Outcomes.

Abbreviations: CCAE, IBM MarketScan^® Commercial Claims and Encounters Data; CVD, cardiovascular disease; GDA, Germany Disease Analyser; IMRD, UK-IQVIA Medical Research Data; MACE, major adverse cardiovascular events; MDCD, IBM Health MarketScan^® Multi-State Medicaid Database; MDCR, IBM Health MarketScan^® Medicare Supplemental and Coordination of Benefits Database; OCEDM, Optum© Clinformatics Extended Data Mart - Date of Death; OEHR, Optum© de-identified Electronic Health Record Dataset; OMOP-CDM, Observational Medical Outcomes Partnership-common data model; SIDIAP, Information System for Research in Primary Care; T2DM, type 2 diabetes mellitus; USOC, United States Open Claims; VA, Department of Veterans Affairs Healthcare System.

Figure 2:. Maximum Standardized Mean Difference Before and After Propensity Score Stratification for All Covariates Across Target-Comparator-Database Combinations.

Abbreviations: CCAE, IBM MarketScan^® Commercial Claims and Encounters Data; DPP4i, dipeptidyl peptidase 4 inhibitor; GDA, Germany Disease Analyzer; GLP1-RA, glucagon-like peptide-1 receptor agonist; IMRD, UK-IQVIA Medical Research Data; MDCD, IBM Health MarketScan^® Multi-State Medicaid Database; IQR, interquartile range; MDCR, IBM Health MarketScan^® Medicare Supplemental and Coordination of Benefits Database; OCEDM, Optum© Clinformatics Extended Data Mart - Date of Death; OEHR, Optum© de-identified Electronic Health Record Dataset; PS, propensity score; SGLT2i, sodium-glucose co-transporter-2 inhibitor; SIDIAP, Information System for Research in Primary Care; SMD, standardized mean difference; SU, Sulfonylurea; USOC, United States Open Claims; VA, Department of Veterans Affairs Healthcare System.

Figure 3:. Meta-analytic Calibrated Hazard Ratio Estimates for Comparative Effectiveness of SGLT2is, GLP1-RAs, DPP4is, and SUs for Cardiovascular Outcomes.

Abbreviations: DPP4i, dipeptidyl peptidase 4 inhibitor; GLP1-RA, glucagon-like peptide-1 receptor agonist; HF, heart failure; HR, hazard ratio; MACE, major adverse cardiovascular events; MI, myocardial infarction; SGLT2i, sodium-glucose co-transporter-2 inhibitor; SU, Sulfonylurea.

Figure 4:. Swarm Plot of Calibrated Hazard Ratio Estimates of Major Outcome Meta-analysis and Leave-one-out Meta-analysis.

Circles depict the calibrated relative risk of each leave-one-out study in which one original data source is removed from the meta-analysis. Diamonds depict the original meta-analysis with all sources. Points are color-coded by major outcomes, y-axis includes the medication comparators, and x-axis on log-scale measures the calibrated relative risk of each outcome-comparator combination. Abbreviations: DPP4i, dipeptidyl peptidase 4 inhibitor; GLP1-RA, glucagon-like peptide-1 receptor agonist; HF, heart failure; MACE, major adverse cardiovascular events; MI, myocardial infarction; SGLT2i, sodium-glucose co-transporter-2 inhibitor; SU, Sulfonylurea.