Primary Occurrence of Cardiovascular Events After Adding Sodium–Glucose Cotransporter-2 Inhibitors or Glucagon-like Peptide-1 Receptor Agonists Compared With Dipeptidyl Peptidase-4 Inhibitors: A Cohort Study in Veterans With Diabetes

Richardson, Tadarro L.; Halvorson, Alese E.; Hackstadt, Amber J.; Hung, Adriana M.; Greevy, Robert A.; Grijalva, Carlos G.; Elasy, Tom A.; Roumie, Christianne L.

doi:10.7326/m22-2751

Cited by 8 publications

(1 citation statement)

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“…A few observational studies have used single data sources to evaluate the cardiovascular outcomes associated with these drugs. [52][53][54][55][56] Moreover, some associations observed in the present study, such as those with DPP4i, contrast with others where the smaller study population may have necessitated studying a combination of drugs directly against SU but challenges isolating an effect. 57 These analyses are limited by local patterns of treatment use and challenges with exposure and outcome ascertainment in individual sources that may confound the observed association of these agents with outcomes.…”

Section: Discussionmentioning

confidence: 69%

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

Khera,

Aminorroaya,

Dhingra

et al. 2024

Preprint

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BackgroundSGLT2 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.MethodsAcross 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.FindingsAcross 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]).InterpretationIn 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.FundingNational Institutes of Health, United States Department of Veterans Affairs

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