SGLT-2 inhibitors, GLP-1 receptor agonists beat DPP-4s, sulfonylureas in pragmatic trial

A pragmatic study compared the effects of sodium-glucose cotransporter-2 (SGLT-2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sulfonylureas on cardiovascular events.

Researchers specified the protocol of a four-arm randomized pragmatic clinical trial and then assembled a cohort of 283,998 patients using Veterans Affairs databases. All included patients had type 2 diabetes treated with metformin and initiated use of SGLT-2 inhibitors (n=46,516), GLP-1 receptor agonists (n=26,038), DPP-4 inhibitors (n=55,310), or sulfonylureas (n=156,134) between Oct 1, 2016, and Sept 30, 2021, and were followed until Dec 31, 2022. The primary outcome was major adverse cardiovascular events (MACE), defined as a composite endpoint of stroke, myocardial infarction, and all-cause mortality. Results were published by The Lancet Diabetes & Endocrinology on July 24.

In intention-to-treat analyses, SGLT-2 inhibitors, GLP-1 receptor agonists, and DPP-4 inhibitors were all associated with lower risk of MACE compared to sulfonylureas, (hazard ratios [HRs], 0.77 [95% CI, 0.74 to 0.80], 0.78 [95% CI, 0.74 to 0.81]), and 0.90 [95% CI, 0.86 to 0.93], respectively). SGLT-2 inhibitors and GLP-1 receptor agonists were associated with lower risk than DPP-4 inhibitors (HRs, 0.86 [95% CI, 0.82 to 0.89] and 0.86 [95% CI, 0.82 to 0.90]), with no significant difference between them. Similarly, per-protocol analyses found lower risk with SGLT-2 inhibitors, GLP-1 receptor agonists, and DPP-4 inhibitors compared to sulfonylureas (HRs, 0.77 [95% CI, 0.73 to 0.82], 0.77 [95% CI, 0.72 to 0.82], and 0.88 [95% CI, 0.83 to 0.93], respectively) and with SGLT-2 inhibitors and GLP-1 receptor agonists compared with DPP-4 inhibitors (HRs, 0.88 [95% CI, 0.8 to 0.93] and 0.88 [95% CI, 0.82 to 0.93], respectively).

“Altogether, the results suggest that compared with both sulfonylureas and DPP-4 inhibitors, both SGLT2 inhibitors and GLP-1 receptor agonists were associated with significantly reduced risk of MACE. The differences in effectiveness of these antihyperglycaemics on risk of MACE could be considered in guiding choice of antihyperglycaemic therapy for type 2 diabetes,” said the study authors. They noted that real-world analyses such as this one are important because randomized controlled trials exclude many patients and usually test medications against placebo rather than alternatives.

An accompanying editorial noted that the study was “the first one that compared different glucose-lowering agents in a population with type 2 diabetes that was not selected a priori” and said that the results could guide choice of diabetes therapy “when the main objective is to reduce cardiovascular morbidity and mortality, although other criteria could be taken into consideration depending on the individual patient profile, safety and tolerance concerns, and the economic context.”