Cardiovascular Effectiveness of Sodium—glucose Cotransporter 2 Inhibitors (SGLT-2i) and Glucagon-like Peptide 1 Receptor Agonists (GLP-1 RA) in Routine Care of Frail People with Type 2 Diabetes

Background: Frailty is important in diabetes management but its impact on the cardiovascular (CV) effectiveness of sodium—glucose cotransporter 2 inhibitors (SGLT-2i) and glucagon-like peptide 1 receptor agonists (GLP-1 RA) as used in routine care is unexplored.

Objectives: To evaluate the CV effectiveness of SGLT-2i, GLP-1 RA, and dipeptidyl peptidase 4 inhibitors (DPP-4i) in older adults with type 2 diabetes (T2D) across different strata of frailty.

Methods: In this comparative effectiveness study using Medicare claims data, we identified three pairwise cohorts of older patients with T2D who initiated a SGLT-2i, a GLP-1 RA, or a DPP-4i between 04/2013-12/2018, and stratified each cohort by three levels of frailty (non-frail, < 0.15; pre-frail, 0.15-0.24; frail, ≥0.25), using a validated claims-based frailty index. Within each frailty stratum, we estimated the propensity score (PS) based on >150 baseline covariates and performed a 1:1 PS matching. The primary outcome was a composite of major adverse cardiovascular events (MACE) including acute myocardial infarction, ischemic stroke, hospitalization for heart failure, and all-cause mortality. For each PS-matched frailty stratum, we estimated hazard ratios (HR), absolute rate differences (RD) per 1`000 person-years, with their 95% confidence intervals (CI), and number needed to treat (NNT). We used the Wald test for homogeneity to assess treatment heterogeneity across frailty strata.

Results: Over a mean follow-up of approximately 9 months, the HR for MACE associated with SGLT-2i vs. DPP-4i (overall, n=91`141 PS-matched pairs; mean age 72.1 years) was 0.82 (95% CI 0.72 to 0.93) in frail, 0.71 (0.67 to 0.75) in pre-frail, and 0.78 (0.71 to 0.86) in non-frail people (p for homogeneity=0.033). The HR for MACE associated with GLP-1 RA vs. DPP-4i (n=90`988 pairs; age 71.8 years) was 0.84 (0.76 to 0.93) in frail, 0.77 (0.73 to 0.81) in pre-frail, and 0.82 (0.74 to 0.91) in non-frail people (p for h.=0.150). The HR for MACE associated with SGLT-2i vs. GLP-1 RA (n=67`067 pairs; age 71.7 years) was 0.87 (0.75 to 1.01) in frail, 0.93 (CI 0.87 to 1.01) in pre-frail, and 0.90 (0.79 to 1.03) in non-frail people (p for h.=0.692). Compared to DPP-4i, the absolute benefit of either SGLT-2i or GLP-1 RA was largest in frail people [RD, -25.0 (-42.1 to -7.9), p for h. < 0.001, NNT=40; and RD, -24.9 (-39.0 to -10.7), p for h. < 0.001, NNT=41; respectively].

Conclusions: In this population-based study of older adults with T2D, while, compared to DPP4i, SGLT-2i and GLP-1 RA were associated with similar relative risk reductions in MACE among people with and without frailty, their absolute benefits were largest in frail people. There was a similar risk of MACE in patients initiating SGLT-2i vs. GLP-1 RA, regardless of frailty level.