SGLT2 Inhibitors, GLP-1 Receptor Agonists Linked to Reduced Risk for MACE

Sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, and dipeptidyl peptidase-4 (DPP-4) inhibitors are associated with decreased risk for major adverse cardiovascular events (MACE) compared with sulfonylureas, according to a study in The Lancet Diabetes & Endocrinology.

The 4-arm randomized pragmatic clinical trial compared the efficacy of SGLT2 inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, or sulfonylureas on the risk for MACE. Data from the US Department of Veterans Affairs (VA) were used to emulate the target trial.

Participants were from the VA Health Care System and had a record of use of any of the 4 drug classes from October 1, 2016, to September 30, 2021, and were followed until December 31, 2022. The primary outcome was MACE, which was the composite of stroke, myocardial infarction, and all-cause mortality.

The final cohort included 283,998 new users (mean age, 64 years; approximately 93% men) of second-line antihyperglycemics from October 1, 2016, to September 30, 2021, with a median follow-up of 3.85 years (IQR, 2.57-5.05). Among the participants, 46,516 initiated use of SGLT2 inhibitors, 26,038 initiated GLP-1 receptor agonists, 55,310 initiated DPP-4 inhibitors, and 156,134 initiated sulfonylureas.

In the intention-to-treat analyses, SGLT2 inhibitors, GLP-1 receptor agonists, and DPP-4 inhibitors were associated with a decreased risk for MACE compared with sulfonylureas (hazard ratio [HR], 0.77 [95% CI, 0.74-0.80]; HR, 0.78 [95% CI, 0.74-0.81]; and HR, 0.90 [95% CI, 0.86-0.93], respectively). SGLT2 inhibitors and GLP-1 receptor agonists were associated with a decreased risk for MACE vs DPP-4 inhibitors (HR, 0.86 [95% CI, 0.82-0.89] and HR, 0.86 [95% CI, 0.82-0.90], respectively). Regarding the risk for MACE in SGLT2 inhibitors vs GLP-1 receptor agonists, the HR was 0.99 (95% CI, 0.94-1.04).

In the per-protocol analysis, SGLT2 inhibitors, GLP-1 receptor agonists, and DPP-4 inhibitors were associated with a decreased risk for MACE vs sulfonylureas (HR, 0.77 [95% CI, 0.73-0.82]; HR, 0.77 [95% CI, 0.72-0.82]; and HR, 0.88 [95% CI, 0.83-0.93], respectively). SGLT2 inhibitors and GLP-1 receptor agonists were associated with a lower risk for MACE vs DPP-4 inhibitors (HR, 0.88 [95% CI, 0.83-0.93] and HR, 0.88 [95% CI, 0.82-0.93], respectively). The risk for MACE in SGLT2 inhibitors vs GLP-1 receptor agonists was associated with an HR of 1.01 (95% CI, 0.94-1.07).

Among several limitations, the study included US veterans who were mostly older, White, and men; residual confounding cannot be completely ruled out; and the results are based on observational data. Also, the cause of death is not assessed, and within-class differences in medications were not investigated.

“These data on differences in effectiveness of these antihyperglycemics on risk of MACE could help to guide choice of antihyperglycemic therapy in people with type 2 diabetes,” stated the investigators.

Disclosure: Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.