medwireNews: Sodium-glucose cotransporter (SGLT)2 inhibitors and glucagon-like peptide (GLP)-1 receptor agonists appear to offer the best protection against major adverse cardiovascular events (MACE) in people with type 2 diabetes, show the results of a randomized target trial emulation.
When compared with sulfonylureas, both SGLT2 inhibitors and GLP-1 receptor agonists were associated with a significant 22–23% lower risk for MACE, defined as a composite of stroke, myocardial infarction, and all-cause mortality, over a median follow-up of 3.85 years, with respective hazard ratios (HRs) of 0.77 and 0.78 in an intent-to-treat (ITT) analysis and 0.77 and 0.77 in a per protocol (PP) analysis.
The absolute risk reductions compared with sulfonylureas per 1000 person–years were 12.34 with SGLT2 inhibitors and 12.07 with GLP-1 receptor agonists.
And, as Ziyad Al-Aly (VA Saint Louis Health Care System, Missouri, USA) and colleagues report in The Lancet Diabetes & Endocrinology, these two drug classes also significantly reduced the occurrence of MACE by 12–14% when compared with dipeptidyl peptidase (DPP)-4 inhibitors (ITT HR=0.86 for both; and PP HR=0.88 for both), with absolute risk reductions per 1000 person–years of 6.97 and 6.68, respectively.
Additionally, there was no significant difference between SGLT2 inhibitors and GLP-1 receptor agonists (ITT HR=0.99; PP HR=1.01) in the reduction of MACE, and DPP-4 inhibitors were also found to reduce MACE to a significantly greater degree than sulfonylureas (ITT HR=0.90; PP HR=0.88).
“These data on differences in effectiveness of these antihyperglycaemics on risk of MACE could help to guide choice of antihyperglycaemic therapy in people with type 2 diabetes,” say the researchers.
They acknowledge that while there have been many cardiovascular outcome trials looking at the effects of antiglycemic medications in people with type 2 diabetes, almost all have used placebo rather than an active agent as a comparator. Only a few have directly compared SGLT2 inhibitors and GLP-1 receptor agonists or have included older drugs such as sulfonylureas or DPP-4 inhibitors, the investigators note.
With clinical data from head-to-head comparisons of multiple antidiabetic agents not currently available and no such clinical trials planned, Al-Aly and co-investigators decided to conduct a pragmatic trial. They used electronic health records from 283,998 new users of antidiabetic agents, namely SGLT2 inhibitors (n=46,516), GLP-1 receptor agonists (n=26,038), DPP-4 inhibitors (n=55,310), and sulfonylureas (n=156,134) to emulate how a four-arm randomized trial might be conducted to see what, if any, cardioprotective differences might exist between the different drug classes.
Al-Aly and co-investigators also looked at the relative safety of the medications, finding that “[c]ompared with sulfonylureas, SGLT2 inhibitors, GLP-1 receptor agonists, and DPP-4 inhibitors were associated with reduced risk of hypoglycemia.”
However, an increased risk for lower limb amputation was found for SGLT2 inhibitors versus sulfonylurea or DPP-4 inhibitor use. SGLT2 inhibitors were also associated with a higher risk for genital infection compared with all other medications evaluated.
André Scheen (CHU Liege, Belgium) comments in a related editorial that while the findings match up with previous studies for the use of SGLT2 inhibitors and GLP-1 receptor antagonists, they are at odds for the sulfonylureas. “The reason for these discrepancies remains unclear,” he observes.
While the authors acknowledge that the results might not be widely generalizable – the patient population was created from a veterans database (92% men, 75% White, average age 64 years) – Scheen notes that the pragmatic trial design provides real-world evidence on the comparative effectiveness of the medications tested.
“The conclusions could guide choice of antihyperglycaemic therapies when the main objective is to reduce cardiovascular morbidity and mortality,” he suggests. However, Scheen notes that “other criteria could be taken into consideration depending on the individual patient profile, safety and tolerance concerns, and the economic context.”
Overall, says Scheen “clinical practice requires personalised therapy for the management of type 2 diabetes.”
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Lancet Diabetes Endocrinol 2023; doi:10.1016/S2213-8587(23)00171-7
Lancet Diabetes Endocrinol 2023; doi:10.1016/S2213-8587(23)00161-4